U.S. patent number 9,492,822 [Application Number 14/942,125] was granted by the patent office on 2016-11-15 for microfluidic feedback using impedance detection.
This patent grant is currently assigned to Advanced Liquid Logic, Inc.. The grantee listed for this patent is ADVANCED LIQUID LOGIC, INC.. Invention is credited to Vijay Srinivasan, Ryan A. Sturmer, Arjun Sudarsan.
United States Patent |
9,492,822 |
Sturmer , et al. |
November 15, 2016 |
Microfluidic feedback using impedance detection
Abstract
Methods comprising measuring the impedance of the electrode
produced by the excitation signal, wherein the impedance indicates
presence of liquid at the electrode are disclosed. Computer
readable mediums storing processor executable instructions for
performing the method, and systems are also disclosed. The systems
comprise a processor, memory and code stored in the memory that
when executed cause the processor at least to: receive an output
voltage signal, superimpose an excitation signal onto the output
voltage signal to produce a superimposed signal, connect the
superimposed signal to an electrode in a droplet actuator, suppress
the output voltage signal, when detecting an impedance of the
electrode, and measure the impedance of the electrode produced by
the excitation signal, wherein the impedance indicates presence of
liquid at the electrode.
Inventors: |
Sturmer; Ryan A. (Durham,
NC), Srinivasan; Vijay (Cary, NC), Sudarsan; Arjun
(Carlsbad, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
ADVANCED LIQUID LOGIC, INC. |
San Diego |
CA |
US |
|
|
Assignee: |
Advanced Liquid Logic, Inc.
(San Diego, CA)
|
Family
ID: |
47139943 |
Appl.
No.: |
14/942,125 |
Filed: |
November 16, 2015 |
Prior Publication Data
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Document
Identifier |
Publication Date |
|
US 20160074863 A1 |
Mar 17, 2016 |
|
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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14116553 |
|
9188615 |
|
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PCT/US2012/036949 |
May 8, 2012 |
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61483827 |
May 9, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01L
3/50273 (20130101); G01N 27/048 (20130101); B01L
3/502792 (20130101); B01L 2300/089 (20130101); G01R
27/16 (20130101); B01L 2200/10 (20130101); B01L
2200/0621 (20130101); B01L 2200/16 (20130101); B01L
2200/14 (20130101); B01L 2300/0829 (20130101); B01L
2400/0427 (20130101); B01L 2300/087 (20130101); B01L
2300/0645 (20130101); B01L 2300/0816 (20130101) |
Current International
Class: |
G01R
27/16 (20060101); B01L 3/00 (20060101); G01N
27/04 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
2006078225 |
|
Mar 2006 |
|
JP |
|
2006317364 |
|
Nov 2006 |
|
JP |
|
2006329899 |
|
Dec 2006 |
|
JP |
|
2006329904 |
|
Dec 2006 |
|
JP |
|
2008096590 |
|
Apr 2008 |
|
JP |
|
0069565 |
|
Nov 2000 |
|
WO |
|
0073655 |
|
Dec 2000 |
|
WO |
|
02080822 |
|
Oct 2002 |
|
WO |
|
2004011938 |
|
Feb 2004 |
|
WO |
|
2004029585 |
|
Apr 2004 |
|
WO |
|
2004030820 |
|
Apr 2004 |
|
WO |
|
2004073863 |
|
Sep 2004 |
|
WO |
|
2005047696 |
|
May 2005 |
|
WO |
|
2005069015 |
|
Jul 2005 |
|
WO |
|
2006003292 |
|
Jan 2006 |
|
WO |
|
2006013303 |
|
Feb 2006 |
|
WO |
|
2006070162 |
|
Jul 2006 |
|
WO |
|
2006081558 |
|
Aug 2006 |
|
WO |
|
2006085905 |
|
Aug 2006 |
|
WO |
|
2006124458 |
|
Nov 2006 |
|
WO |
|
2006127451 |
|
Nov 2006 |
|
WO |
|
2006129486 |
|
Dec 2006 |
|
WO |
|
2006132211 |
|
Dec 2006 |
|
WO |
|
2006134307 |
|
Dec 2006 |
|
WO |
|
2006138543 |
|
Dec 2006 |
|
WO |
|
2007003720 |
|
Jan 2007 |
|
WO |
|
2007012638 |
|
Feb 2007 |
|
WO |
|
2007033990 |
|
Mar 2007 |
|
WO |
|
2007048111 |
|
Apr 2007 |
|
WO |
|
2007120240 |
|
Oct 2007 |
|
WO |
|
2007120241 |
|
Oct 2007 |
|
WO |
|
2007123908 |
|
Nov 2007 |
|
WO |
|
2008051310 |
|
May 2008 |
|
WO |
|
2008055256 |
|
May 2008 |
|
WO |
|
2008068229 |
|
Jun 2008 |
|
WO |
|
2008091848 |
|
Jul 2008 |
|
WO |
|
2008098236 |
|
Aug 2008 |
|
WO |
|
2008101194 |
|
Aug 2008 |
|
WO |
|
WO 2008/101194 |
|
Aug 2008 |
|
WO |
|
2008106678 |
|
Sep 2008 |
|
WO |
|
2008109664 |
|
Sep 2008 |
|
WO |
|
2008112856 |
|
Sep 2008 |
|
WO |
|
2008116209 |
|
Sep 2008 |
|
WO |
|
2008116221 |
|
Sep 2008 |
|
WO |
|
2008118831 |
|
Oct 2008 |
|
WO |
|
2008124846 |
|
Oct 2008 |
|
WO |
|
2008131420 |
|
Oct 2008 |
|
WO |
|
2008134153 |
|
Nov 2008 |
|
WO |
|
2009002920 |
|
Dec 2008 |
|
WO |
|
2009003184 |
|
Dec 2008 |
|
WO |
|
2009011952 |
|
Jan 2009 |
|
WO |
|
2009021173 |
|
Feb 2009 |
|
WO |
|
2009021233 |
|
Feb 2009 |
|
WO |
|
2009026339 |
|
Feb 2009 |
|
WO |
|
2009029561 |
|
Mar 2009 |
|
WO |
|
2009032863 |
|
Mar 2009 |
|
WO |
|
2009052095 |
|
Apr 2009 |
|
WO |
|
2009052123 |
|
Apr 2009 |
|
WO |
|
2009052321 |
|
Apr 2009 |
|
WO |
|
2009052345 |
|
Apr 2009 |
|
WO |
|
2009052348 |
|
Apr 2009 |
|
WO |
|
2009076414 |
|
Jun 2009 |
|
WO |
|
2009086403 |
|
Jul 2009 |
|
WO |
|
2009111769 |
|
Sep 2009 |
|
WO |
|
2009135205 |
|
Nov 2009 |
|
WO |
|
2009137415 |
|
Nov 2009 |
|
WO |
|
2009140373 |
|
Nov 2009 |
|
WO |
|
2009140671 |
|
Nov 2009 |
|
WO |
|
2010004014 |
|
Jan 2010 |
|
WO |
|
2010006166 |
|
Jan 2010 |
|
WO |
|
2010009463 |
|
Jan 2010 |
|
WO |
|
2010019782 |
|
Feb 2010 |
|
WO |
|
2010027894 |
|
Mar 2010 |
|
WO |
|
2010042637 |
|
Apr 2010 |
|
WO |
|
2010077859 |
|
Jul 2010 |
|
WO |
|
2011002957 |
|
Jan 2011 |
|
WO |
|
2011020011 |
|
Feb 2011 |
|
WO |
|
2011046615 |
|
Apr 2011 |
|
WO |
|
2011057197 |
|
May 2011 |
|
WO |
|
2011084703 |
|
Jul 2011 |
|
WO |
|
2011126892 |
|
Oct 2011 |
|
WO |
|
2012009320 |
|
Jan 2012 |
|
WO |
|
2012012090 |
|
Jan 2012 |
|
WO |
|
2012037308 |
|
Mar 2012 |
|
WO |
|
2012068055 |
|
May 2012 |
|
WO |
|
2013009927 |
|
Jan 2013 |
|
WO |
|
Other References
Benton et al., "Library Preparation Method 1 DNA Library
Construction for Illumina SBS Sequencing Platforms using
NEBNext.RTM. Library Preparation Reagents", Application Note,
NuGEN, 2011. cited by applicant .
Boles et al., "Droplet-Based Pyrosequencing Using Digital
Microfluidics", Analytical Chemistry, vol. 83, Sep. 2011, 8439-47.
cited by applicant .
Bottausci et al., "Fully Integrated EWOD Based Bio-Analysis
Device", Labautomation 2011, Palm Springs Convention Center, Palm
Springs, CA, USA; Abstract in Proceedings on line, poster
distributed, Jan. 29-Feb. 2, 2011. cited by applicant .
Burde et al., "Digital Microfluidic Rapid HIV Point-of-Care
Diagnostic Device for Resource Limited Settings", Workshop on TB
and HIV Diagnostics, Silver Spring, MD. (Poster, copies distributed
to attendees.)
http://www.blsmeetings.net/TB-HIV-DX-Wkshop/index.cfm, Jun. 28,
2011. cited by applicant .
Burton et al., "Diagnosis of Fabry and Gaucher diseases from the
Pilot Screening of Newborns for Lysosomal Storage Disorders in
Illinois", APHL Newborn Screening and Genetic Testing Symposium,
San Diego, 2011. cited by applicant .
Chakrabarty, "Automated Design of Microfluidics-Based Biochips:
connecting Biochemistry of Electronics CAD", IEEE International
Conference on Computer Design, San Jose, CA, Oct. 1-4, 2006,
93-100. cited by applicant .
Chakrabarty et al., "Design Automation Challenges for
Microfluidics-Based Biochips", DTIP of MEMS & MOEMS, Montreux,
Switzerland, Jun. 1-3, 2005. cited by applicant .
Chakrabarty et al., "Design Automation for Microfluidics-Based
Biochips", ACM Journal on Engineering Technologies in Computing
Systems , 1(3), Oct. 2005, 186-223. cited by applicant .
Chakrabarty, "Design, Testing, and Applications of Digital
Microfluidics-Based Biochips", Proceedings of the 18th
International Conf. on VLSI held jointly with 4th International
Conf. on Embedded Systems Design (VLSID'05), IEEE, Jan. 3-7, 2005.
cited by applicant .
Chen et al., "Development of Mesoscale Actuator Device with Micro
Interlocking Mechanism", J. Intelligent Material Systems and
Structures, vol. 9, No. 4, Jun. 1998, pp. 449-457. cited by
applicant .
Chen et al., "Mesoscale Actuator Device with Micro Interlocking
Mechanism", Proc. IEEE Micro Electro Mechanical Systems Workshop,
Heidelberg, Germany, Jan. 1998, pp. 384-389. cited by applicant
.
Chen et al., "Mesoscale Actuator Device: Micro Interlocking
Mechanism to Transfer Macro Load", Sensors and Actuators, vol. 73,
Issues 1-2, Mar. 1999, pp. 30-36. cited by applicant .
Cohen, "Automated Multianalyte Screening Tool for Classification of
Forensic Samples", NIJ conference 2012,
http://www.nij.gov/nij/events/nij.sub.--conference/2012/nij-2012-program--
book.pdf, 2012. cited by applicant .
Cohen, "Digital Microfluidic Sample Prep & Bioanalytical
Systems", BioDot Workshop: From R&D to Quantitative IVDs,
Irvine, CA, Apr. 24, 2012. cited by applicant .
Cotten et al., "Digital Microfluidics: a novel platform for
multiplexed detection of lysosomal storage diseases", Abstract #
3747.9. Pediatric Academic Society Conference, 2008. cited by
applicant .
Delapierre et al., "SmartDrop: An Integrated System from Sample
Collection to Result using real-time PCR," 4th National Bio-Threat
Conference, Dec. 7-9, 2010, New Orleans, LA, USA; Abstract in
Proceedings, Poster presented at conference. cited by applicant
.
Delattre, Movie in news on TF1 (at 12'37'' Cyril Delattre),
http://videos.tf1.fr/jt-we/zoom-sur-grenoble-6071525.html, 2009,
(English translation of audio). cited by applicant .
Delattre, Movie in talk show "C Dans l'air" (at 24'' Cyril
Delattre),
http://www.france5.fr/c-dans-l-air/sante/bientot-vous-ne-serez-plus-malad-
e-31721, 2009, (English translation of audio). cited by applicant
.
Delattre, Movie on Web TV--Cite des sciences (at 3'26'' Cyril
Delattre),
http://www.universcience.tv/video-laboratorie-de-poche-793.html,
2009, (English translation of audio). cited by applicant .
Delattre et al., "Macro to microfluidics system for biological
environmental monitoring", Biosensors and Bioelectronics, vol. 36,
Issue 1, 2012, Available online, Apr. 27, 2012, 230-235. cited by
applicant .
Delattre et al., "SmartDrop: an integrated system from sample
preparation to analysis using real-time PCR", 10th International
Symposium on Protection against Chemical and Biological Warfare
Agents; Stockholm, Sweden; poster, Jun. 10, 2010. cited by
applicant .
Delattre et al., "SmartDrop: An integrated system from sample
preparation to analysis using real-time PCR", 10th International
Symposium on Protection against Chemical and Biological Warfare
Agents; Stockholm, Sweden; Abstract,paper,, Jun. 8-11, 2010. cited
by applicant .
Delattre et al., "Towards an industrial fabrication process for
electrowetting chip using standard MEMS Technology", .mu.TAS2008,
San Diego; poster presented, Oct. 15, 2008. cited by applicant
.
Delattre et al., "Towards an industrial fabrication process for
electrowetting chip using standard MEMS Technology", .mu.TAS2008,
San Diego; Abstract in proceedings, Oct. 13-16, 2008, 1696-1698.
cited by applicant .
Dewey, "Towards a Visual Modeling Approach to Designing
Microelectromechanical System Transducers", Journal of
Micromechanics and Microengineering, vol. 9, Dec. 1999, 332-340.
cited by applicant .
Dewey et al., "Visual modeling and design of microelectromechanical
system tansducers", Microelectronics Journal, vol. 32, Apr. 2001,
373-381. cited by applicant .
Eckhardt et al., "Development and validation of a single-step
fluorometric assay for Hunter syndrome", APHL Newborn Screening and
Genetic Testing Symposium, San Diego, 2011. cited by applicant
.
Emani et al., "Novel microfluidic platform for automated
lab-on-chip testing of hypercoagulability panel", Blood Coagulation
and Fibrinolysis, vol. 23(8), 2012, 760-8. cited by applicant .
Emani et al., "Novel Microfluidic Platform for Point of Care
Hypercoagulability Panel Testing", Circulation, vol. 122, 2010,
A14693. cited by applicant .
Fair et al., "A Micro- Watt Metal-Insulator-Solution-Transport
(MIST) Device for Scalable Digital Bio-Microfluidic Systems", IEEE
IEDM Technical Digest, 2001, 16.4.1-4. cited by applicant .
Fair et al., "Advances in droplet-based bio lab-on-a-chip",
BioChips 2003, Boston, 2003. cited by applicant .
Fair et al., "Bead-Based and Solution-Based Assays Performed on a
Digital Microfluidic Platform", Biomedical Engineering Society
(BMES) Fall Meeting, Baltimore, MD, Oct. 1, 2005. cited by
applicant .
Fair, "Biomedical Applications of Electrowetting Systems", 5th
International Electrowetting Workshop, Rochester, NY, May 31, 2006.
cited by applicant .
Fair et al., "Chemical and Biological Applications of
Digital-Microfluidic Devices", IEEE Design & Test of Computers,
vol. 24(1), Jan.-Feb. 2007, 10-24. cited by applicant .
Fair et al., "Chemical and biological pathogen detection in a
digital microfluidic platform", DARPA Workshop on Microfluidic
Analyzers for DoD and National Security Applications, Keystone, CA,
2006. cited by applicant .
Fair, "Digital microfluidics: is a true lab-on-a-chip possible?",
Microfluid Nanofluid, vol. 3, Mar. 8, 2007, 245-281. cited by
applicant .
Fair, "Droplet-based microfluidic Genome sequencing", NHGRI PI's
meeting, Boston, 2005. cited by applicant .
Fair et al., "Electrowetting-based On-Chip Sample Processing for
Integrated Microfluidics", IEEE Inter. Electron Devices Meeting
(IEDM), 2003, 32.5.1-32.5.4. cited by applicant .
Fair et al., "Integrated chemical/biochemical sample collection,
pre-concentration, and analysis on a digital microfluidic
lab-on-a-chip platform", Lab-on-a-Chip: Platforms, Devices, and
Applications, Conf. 5591, SPIE Optics East, Philadelphia, Oct.
25-28, 2004. cited by applicant .
Fair, "Scaling of Digital Microfluidic Devices for Picoliter
Applications", The 6th International Electrowetting Meeting, Aug.
20-22, 2008, p. 14. cited by applicant .
Fouillet, "Bio-Protocol Integration in Digital Microfluidic Chips",
The 6th International Electrowetting Meeting, Aug. 20-22, 2008, p.
15. cited by applicant .
Fouillet et al., "Design and Validation of a Complex Generic
Fluidic Microprocessor Based on EWOD Droplet for Biological
Applications", 9th International Conference on Miniaturized Systems
for Chem and Life Sciences, Boston, MA, Oct. 9-13, 2005, 58-60.
cited by applicant .
Fouillet et al., "Digital microfluidic design and optimization of
classic and new fluidic functions for lab on a chip systems",
Microfluid Nanofluid, vol. 4, 2008, 159-165. cited by applicant
.
Graham et al., "Development of Quality Control Spots for Lysosomal
Storage Disorders under cGMP", APHL Newborn Screening and Genetic
Testing Symposium, San Diego, 2011. cited by applicant .
Hua et al., "Multiplexed real-time polymerase chain reaction on a
digital microfluidic platform", Analytical Chemistry, vol. 82, No.
6, Mar. 15, 2010, Published on Web, Feb. 12, 2010, 2310-2316. cited
by applicant .
Hua et al., "Rapid Detection of Methicillin-Resistant
Staphylococcus aureus (MRSA) Using Digital Microfluidics", 12th
Intl Conference on Miniaturized Systems for Chemistry and Life
Sciences, Proc. .mu.TAS, Oct. 12-16, 2008. cited by applicant .
Jary et al., "Development of complete analytical system for
Environment and homeland security", 14th International Conference
on Biodetection Technologies 2009, Technological Responses to
Biological Threats, Baltimore, MD; Abstract in Proceedings, poster
distributed at conference, Jun. 25-26, 2009, 663. cited by
applicant .
Jary et al., "SmartDrop, Microfluidics for Biology", Forum 4i 2009,
Grenoble, France; Flyer distributed at booth, May 14, 2009. cited
by applicant .
Jinks et al., "Newborn Screening for Krabbe and other Lysosomal
Storage Diseases", The 3rd Annual Workshop on Krabbe Disease, Java
Center, New York, Jul. 19-21, 2010. cited by applicant .
Jun et al., "Valveless Pumping using Traversing Vapor Bubbles in
Microchannels", J. Applied Physics, vol. 83, No. 11, Jun. 1998, pp.
5658-5664. cited by applicant .
Kim et al., "MEMS Devices Based on the Use of Surface Tension",
Proc. Int. Semiconductor Device Research Symposium (ISDRS'99),
Charlottesville, VA, Dec. 1999, pp. 481-484. cited by applicant
.
Kim, "Microelectromechanical Systems (MEMS) at the UCLA
Micromanufacturing Lab", Dig. Papers, Int. Microprocesses and
Nanotechnology Conf. (MNC'98), Kyungju, Korea, Jul. 1998, pp.
54-55. cited by applicant .
Kim et al., "Micromachines Driven by Surface Tension", AIAA
99/3800, 30th AIAA Fluid Dynamics Conference, Norfolk, VA, (Invited
lecture), Jun. 1999, pp. 1-6. cited by applicant .
Kleinert et al., "Dynamics and Stability of Oil Films During
Droplet Transport by Electrowetting", 86th ACS Colloid &
Surface Science Symposium, Abstract, Jun. 13, 2012. cited by
applicant .
Kleinert et al., "Dynamics and Stability of Oil Films During
Droplet Transport by Electrowetting", 86th ACS Colloid &
Surface Science Symposium, Presentation, Jun. 13, 2012. cited by
applicant .
Kleinert et al., "Dynamics and stability of oil films during
droplet transport by electrowetting", 8th International Meeting on
Electrowetting, Athens, Greece, Jun. 21-23, 2012. cited by
applicant .
Kleinert et al., "Electric Field Assisted Convective Assembly of
Colloidal Crystal Coatings", Symposium MM: Evaporative Self
Assembly of Polymers, Nanoparticles, and DNA, 2010 MRS Spring
Meeting, San Francisco, CA., Apr. 6-8, 2010. cited by applicant
.
Kleinert et al., "Electric Field-Assisted Convective Assembly of
Large-Domain Colloidal Crystals", The 82nd Colloid & Surface
Science Symposium, ACS Division of Colloid & Surface Science,
North Carolina State University, Raleigh, NC.
www.colloids2008.org., Jun. 15-18, 2008. cited by applicant .
Kleinert, "Electric-Field-Assisted Convective Assembly of Colloidal
Crystal Coatings", Langmuir, vol. 26(12), May 13, 2010,
10380-10385. cited by applicant .
Lee et al., "Microactuation by Continuous Electrowetting Phenomenon
and Silicon Deep Rie Process", Proc. MEMS (DSC--vol. 66) ASME Int.
Mechanical Engineering Congress and Exposition, Anaheim, CA, Nov.
1998, 475-480. cited by applicant .
Lee et al., "Liquid Micromotor Driven by Continuous
Electrowetting", Proc. IEEE Micro Electro Mechanical Systems
Workshop, Heidelberg, Germany, Jan. 1998, pp. 538-543. cited by
applicant .
Lee et al., "Theory and Modeling of Continuous Electrowetting
Microactuation", Proc. MEMS (MEMS-vol. 1), ASME Int. Mechanical
Engineering Congress and Exposition, Nashville, TN, Nov. 1999, pp.
397-403. cited by applicant .
Malk et al., "EWOD in coplanar electrode configurations",
Proceedings of ASME 2010 3rd Joint US-European Fluids Engineering
Summer Meeting and 8th International Conference on Nanochannels,
Microchannels, and Minichannels,
http://asmedl.org/getabs/servlet/GetabsServlet?prog=normal&id=ASMECP00201-
005450100023900000, Aug. 1-5, 2010. cited by applicant .
Marchand et al., "Organic Synthesis in Soft Wall-Free
Microreactors: Real-Time Monitoring of Fluorogenic Reactions",
Analytical Chemistry, vol. 80, Jul. 2, 2008, 6051-6055. cited by
applicant .
Millington et al., "Applications of tandem mass spectrometry and
microfluidics in newborn screening", Southeastern Regional Meeting
of the American Chemical Society, Raleigh, North Carolina, 2012.
cited by applicant .
Millington et al., "Digital microfluidics: a future technology in
the newborn screening laboratory", Seminars in Perinatology, vol.
34, Apr. 2010, 163-169. cited by applicant .
Millington et al., "Digital Microfluidics: a novel platform for
multiplexed detection of LSDs with potential for newborn
screening", Association of Public Health Laboratories Annual
Conference, San Antonio, TX, Nov 4, 2008. cited by applicant .
Millington et al., "Digital Microfluidics: A Novel Platform for
Multiplexing Assays Used in Newborn Screening", Proceedings of
the7th International and Latin American Congress. Oral
Presentations. Rev Invest Clin; vol. 61 (Supl. 1), 2009, 21-33.
cited by applicant .
Mugele et al., "Electrowetting: from basics to applications",
Institution of Physics Publishing, Journal of Physics: Condensed
Matter, 2005, R705-R774. cited by applicant .
Paik et al., "A digital-microfluidic approach to chip cooling",
IEEE Design & Test of Computers, vol. 25, Jul. 2008, 372-381.
cited by applicant .
Paik et al., "Adaptive Cooling of Integrated Circuits Using Digital
Microfluidics", IEEE Transactions on VLSI, vol. 16, No. 4, 2008,
432-443. cited by applicant .
Paik et al., "Adaptive Cooling of Integrated Circuits Using Digital
Microfluidics", accepted for publication in IEEE Transactions on
VLSI Systems, 2007, and Artech House, Norwood, MA, 2007. cited by
applicant .
Paik, "Adaptive Hot-Spot Cooling of Integrated Circuits Using
Digital Microfluidics", Dissertation, Dept. of Electrical and
Computer Engineering, Duke University, Apr. 25, 2006, 1-188. cited
by applicant .
Paik et al., "Adaptive hot-spot cooling of integrated circuits
using digital microfluidics", Proceedings ASME International
Mechanical Engineering Congress and Exposition, Orlando, Florida,
USA. IMECE2005-81081, Nov. 5-11, 2005, 1-6. cited by applicant
.
Paik et al., "Coplanar Digital Microfluidics Using Standard Printed
Circuit Board Processes", 9th International Conference on
Miniaturized Systems for Chemistry and Life Sciences (MicroTAS),
Boston, MA; Poster, 2005. cited by applicant .
Paik et al., "Coplanar Digital Microfluidics Using Standard Printed
Circuit Board Processes", 9th Int'l Conf. on Miniaturized Systems
for Chemistry and Life Sciences, Boston, MA, Oct. 9-13, 2005,
566-68. cited by applicant .
Paik et al., "Droplet-Based Hot Spot Cooling Using Topless Digital
Microfluidics on a Printed Circuit Board", Int'l Workshops on
Thermal Investigations of ICs and Systems (THERMINIC), 2005,
278-83. cited by applicant .
Paik et al., "Electrowetting-based droplet mixers for microfluidic
systems", Lab on a Chip (LOC), vol. 3. (more mixing videos
available, along with the article, at LOC's website), 2003, 28-33.
cited by applicant .
Paik et al., "Programmable Flow-Through Real Time PCR Using Digital
Microfluidics", 11th International Conference on Miniaturized
Systems for Chemistry and Life Sciences, Paris, France, Oct. 7-11,
2007, 1559-1561. cited by applicant .
Paik et al., "Programmable flow-through real-time PCR using digital
microfluidics", Proc. Micro Total Analysis Systems (.mu.TAS),
Handout, 2007. cited by applicant .
Paik et al., "Programmable flow-through real-time PCR using digital
microfluidics", Proc. Micro Total Analysis Systems (.mu.TAS),
Poster, 2007. cited by applicant .
Paik et al., "Rapid Droplet Mixers for Digital Microfluidic
Systems", Masters Thesis, Duke Graduate School., 2002, 1-82. cited
by applicant .
Paik et al., "Rapid droplet mixers for digital microfluidic
systems", Lab on a Chip, vol. 3. (More mixing videos available,
along with the article, at LOC's website.), 2003, 253-259. cited by
applicant .
Paik et al., "Thermal effects on Droplet Transport in Digital
Microfluids with Application to Chip Cooling Processing for
Integrated Microfluidics", International Conference on Thermal,
Mechanics, and Thermomechanical Phenomena in Electronic Systems
(ITherm), 2004, 649-654. cited by applicant .
Pamula, "A digital microfluidic platform for multiplexed explosive
detection", Chapter 18, Electronics Noses and Sensors for the
Detection of Explosives, Eds., J.W. Gardner and J. Yinon, Kluwer
Academic Publishers, 2004. cited by applicant .
Pamula et al., "A droplet-based lab-on-a-chip for colorimetric
detection of nitroaromatic explosives", Proceedings of Micro
Electro Mechanical Systems, 2005, 722-725. cited by applicant .
Pamula et al., "Cooling of integrated circuits using droplet-based
microfluidics", Proc. ACM Great Lakes Symposium on VLSI, Apr. 2003,
84-87. cited by applicant .
Pamula, "Digital microfluidic lab-on-a-chip for multiplexing tests
in newborn screening", Newborn Screening Summit: Envisioning a
Future for Newborn Screening, Bethesda, MD, Dec. 7, 2009. cited by
applicant .
Pamula et al., "Digital microfluidic lab-on-a-chip for protein
crystallization", 5th Protein Structure Initiative "Bottlenecks"
Workshop, NIH, Bethesda, MD, Apr. 13-14, 2006, I-16. cited by
applicant .
Pamula et al., "Digital Microfluidic Methods in Diagnosis of
Neonatal Biochemical Abnormalities", Developing Safe and Effective
Devices and Instruments for Use in the Neonatal Intensive Care for
the 21st Century, Pediatric Academic Societies' Annual Meeting,
Vancouver, Canada, May 1-4, 2010. cited by applicant .
Pamula et al., "Digital Microfluidic Platform for Multiplexing LSD
Assays in Newborn Screening", LSD World Meeting, Las Vegas, NV,
Feb. 16-18, 2011. cited by applicant .
Pamula et al., "Digital Microfluidics Platform for Lab-on-a-chip
applications", Duke University Annual Post Doctoral Research Day,
2002. cited by applicant .
Pamula et al., "Microfluidic electrowetting-based droplet mixing",
IEEE, 2002, 8-10. cited by applicant .
Pamula et al., "Rapid LSD assays on a multiplex digital
microfluidic platform for newborn screening", Lysosomal Disease
Network World Symposium 2012, San Diego, CA, Feb. 8-19, 2012, 39.
cited by applicant .
Pamula, "Sample Preparation and Processing using Magnetic Beads on
a Digital Microfluidic Platform", CHI's Genomic Sample Prep, San
Francisco, CA, Jun. 9-10, 2009. cited by applicant .
Pamula, "Sample-to-sequence-molecular diagnostics on a digital
microfluidic lab on a chip", Pre-conference workshops, 4th
International Conference on Birth Defects and Disabilities in the
Developing World, New Dehli, India, Oct. 4, 2009. cited by
applicant .
Pollack et al., "Applications of Electrowetting-Based Digital
Microfluidics in Clinical Diagnostics", Expert Rev. Mol. Diagn.,
vol. 11(4), 2011, 393-407. cited by applicant .
Pollack et al., "Continuous sequencing-by-synthesis-based on a
digital microfluidic platform", National Human Genome Research
Institute, Advanced DNA Sequencing Technology Development Meeting,
Chapel Hill, NC, Mar. 10-11, 2010. cited by applicant .
Pollack, et al., "Electrowetting-Based Actuation of Droplets for
Integrated Microfluidics", Lab on a Chip (LOC), vol. 2, 2002,
96-101. cited by applicant .
Pollack et al., "Electrowetting-based actuation of liquid droplets
for microfluidic applications", Appl. Phys. Letters, vol. 77, No.
11, Sep. 11, 2000, 1725-1726. cited by applicant .
Pollack, "Electrowetting-based Microactuation of Droplets for
Digital Microfluidics", PhD Thesis, Department of Electrical and
Computer Engineering, Duke University, 2001. cited by applicant
.
Pollack et al., "Electrowetting-Based Microfluidics for
High-Throughput Screening", smallTalk 2001 Conference Program
Abstract, San Diego, Aug. 27-31, 2001, 149. cited by applicant
.
Pollack et al., "Investigation of electrowetting-based
microfluidics for real-time PCR applications", Proc. 7th Int'l
Conference on Micro Total Analysis Systems (mTAS), Squaw Valley,
CA, Oct. 5-9, 2003, 619-622. cited by applicant .
Pollack, "Lab-on-a-chip platform based digital microfluidics", The
6th International Electrowetting Meeting, Aug. 20-22, 2008, 16.
cited by applicant .
Pollack, "Sample Preparation Using Digital Microfluidics", Sample
Prep 2012, Knowledge Press, Inc., May 3-4, 2012. cited by applicant
.
Punnamaraju, "Voltage and Photo Induced Effects in
Droplet-Interface-Bilayer Lipid", PhD Thesis, University of
Cincinnati, 2011. cited by applicant .
Punnamaraju et al., "Voltage Control of Droplet Interface Bilayer
Lipid Membrane Dimensions", Langmuir The ACS Journal of Surfaces
and Colloids, vol. 27, Issue 2, 2011, Published on Web, Dec. 10,
2010, 618-626. cited by applicant .
Ren et al., "Automated electrowetting-based droplet dispensing with
good reproducibility", Proc. Micro Total Analysis Systems (mTAS),
7th Int. Conf.on Miniaturized Chem and Biochem Analysis Systems,
Squaw Valley, CA, Oct. 5-9, 2003, 993-996. cited by applicant .
Ren et al., "Automated on-chip droplet dispensing with volume
control by electro-wetting actuation and capacitance metering",
Sensors and Actuators B: Chemical, vol. 98, Mar. 2004, 319-327.
cited by applicant .
Ren et al., "Design and testing of an interpolating mixing
architecture for electrowetting-droplet-on-chip chemical dilution",
Transducers, 12th International Conference on Solid-State Sensors,
Actuators and Microsystems, 2003, 619-622. cited by applicant .
Ren et al., "Dynamics of electro-wetting droplet transport",
Sensors and Actuators B (Chemical), vol. B87, No. 1, Nov. 15, 2002,
201-206. cited by applicant .
Ren et al., "Micro/Nano Liter Droplet Formation and Dispensing by
Capacitance Metering and Electrowetting Actuation", IEEE-NANO,
2002, 369-372. cited by applicant .
Rival et al., "EWOD Digital Microfluidic Device for Single Cells
Sample Preparation and Gene Expression Analysis", Lab Automation
2010, Palm Springs Convention Center, Palm Springs, CA, USA;
Abstract in Proceedings, Poster distributed at conference, Jan.
23-27, 2010. cited by applicant .
Rival et al., "Expression de genes de quelques cellules sur puce
EWOD/Gene expression of few cells on EWOD chip",
iRTSV,http://www-dsv.cea.fr/var/plain/storage/original/media/File/iRTSV/t-
hema.sub.--08(2).pdf (english translation), Winter 2009-2010. cited
by applicant .
Rival et al., "New insight on droplet dynamics under electrowetting
actuation and design tools for speeding up product development",
8th Electrowetting Workshop, Athens, Greece. Abstract, 2012. cited
by applicant .
Rival et al., "New insight on droplet dynamics under electrowetting
actuation and design tools for speeding up product development",
8th Electrowetting Workshop, Athens, Greece, Presentation, 2012.
cited by applicant .
Rival et al., "Towards Single Cells Gene Expression on EWOD Lab on
Chip", ESONN 2008, Grenoble, France; Poster presented, Aug. 26,
2008. cited by applicant .
Rival et al., "Towards single cells gene expression on EWOD lab on
chip", ESONN, Grenoble, France, abstract in proceedings, Aug. 2008.
cited by applicant .
Rival et al., "Towards single cells gene expression preparation and
analysis on ewod lab on chip", Nanobio Europe 2009, Poster
distributed at conference, Jun. 16-18, 2009. cited by applicant
.
Rival et al., "Towards single cells gene expression preparation and
analysis on ewod lab on chip", Nanobio Europe 2009, Abstract in
proceedings, Jun. 16-18, 2009. cited by applicant .
Rival et al., "Towards single cells gene expression preparation and
analysis on ewod lab on chip", Lab on Chip Europe 2009 poster
distributed at Conference, May 19-20, 2009. cited by applicant
.
Rival et al., "Towards single cells gene expression preparation and
analysis on ewod lab on chip", Lab on Chip Europe 2009, Abstract in
proceedings, May 19-20, 2009. cited by applicant .
Rouse et al., "Digital microfluidics: a novel platform for
multiplexing assays used in newborn screening", Poster 47, 41st
AACC's Annual Oak Ridge Conference Abstracts, Clinical Chemistry,
vol. 55, 2009, 1891. cited by applicant .
Schell et al., "Evaluation of a Digital Microfluidic real-time PCR
Platform to detect DNA of Candida albicans", Eur. J. Clin Microbiol
Infect Dis, Published on-line DOI 10.1007/S10096-012-15616, Feb.
2012. cited by applicant .
Sherman et al., "Flow Control by Using High-Aspect-Ratio, In-Plane
Microactuators", Sensors and Actuators, vol. 73, 1999, pp. 169-175.
cited by applicant .
Sherman et al., "In-Plane Microactuator for Fluid Control
Application", Proc. IEEE Micro Electro Mechanical Systems Workshop,
Heidelberg, Germany, Jan. 1998, pp. 454-459. cited by applicant
.
Shi et al., "Evaluation of stability of fluorometric reagent kits
for screening of Lysosomal Storage Disorders", APHL Newborn
Screening and Genetic Testing Symposium, San Diego, 2011. cited by
applicant .
Sista et al., "96-Immunoassay Digital Microfluidic Multiwell
Plate", Proc. .mu.TAS, Oct. 12-16, 2008. cited by applicant .
Sista, "Development of a Digital Microfluidic Lab-on-a-Chip for
Automated Immunoassays with Magnetically Responsive Beads", PhD
Thesis, Department of Chemical Engineering, Florida State
University, 2007. cited by applicant .
Sista et al., "Development of a digital microfluidic platform for
point of care testing", Lab on a chip, vol. 8, Dec. 2008, First
published as an Advance Article on the web, Nov. 5, 2008,
2091-2104. cited by applicant .
Sista et al., "Digital Microfluidic Platform for Multiplexing
Enzyme Assays: Implications for Lysosomal Storage Disease Screening
in Newborns", Clinical Chemistry, vol. 57, Aug. 22, 2011, 1444-51.
cited by applicant .
Sista et al., "Digital Microfluidic platform for multiplexing LSD
assays in newborn screening", APHL Newborn Screening and Genetic
Testing Symposium, Orlando, May 3-6, 2010. cited by applicant .
Sista et al., "Heterogeneous immunoassays using magnetic beads on a
digital microfluidic platform", Lab on a Chip, vol. 8, Dec. 2008,
First published as an Advance Article on the web, Oct. 14, 2008,
2188-2196. cited by applicant .
Sista et al., "Multiplex Digital Microfluidic Platform for Rapid
Newborn Screening of Lysosomal Storage Disorders", ACMG Annual
Meeting, Charlotte, NC, 2012. cited by applicant .
Sista et al., "Performance of a digital microfluidic assay for
Gaucher and Hurler disorders", APHL Newborn Screening and Genetic
Testing Symposium, San Diego, 2011. cited by applicant .
Sista et al., "Rapid, Single-Step Assay for Hunter Syndrome in
Dried Blood Spots Using Digital Microfluidics", Clinica Chimica
Acta, vol. 412, 2011, 1895-97. cited by applicant .
Sista et al., "Spatial multiplexing of immunoassays for
small-volume samples", 10th PI Meeting IMAT, Bethesda, 2009. cited
by applicant .
Srinivasan et al., "3-D imaging of moving droplets for
microfluidics using optical coherence tomography", Proc. 7th
International Conference on Micro Total Analysis Systems (mTAS),
Squaw Valley, CA, Oct. 5-9, 2003, 1303-1306. cited by applicant
.
Srinivasan et al., "A digital microfluidic biosensor for
multianalyte detection", Proc. IEEE 16th Annual Int'l Conf. on
Micro Electro Mechanical Systems Conference, 2003, 327-330. cited
by applicant .
Srinivasan, "A Digital Microfluidic Lab-on-a-Chip for Clinical
Diagnostic Applications", Ph.D. thesis, Dept of Electrical and
Computer Engineering, Duke University, 2005,. cited by applicant
.
Srinivasan et al., "An integrated digital microfluidic
lab-on-a-chip for clinical diagnostics on human physiological
fluids", Lab on a Chip, vol. 4, 2004, 310-315. cited by applicant
.
Srinivasan et al., "Clinical diagnostics on human whole blood,
plasma, serum, urine, saliva, sweat and tears on a digital
microfluidic platform", Proc. 7th International Conference on Micro
Total Analysis Systems (mTAS), Squaw Valley, CA, Oct. 5-9, 2003,
1287-1290. cited by applicant .
Srinivasan et al., "Commercializing electrowetting-based digital
microfluidics: from the lab to a product", 8th International
Meeting on Electrowetting, Athens, Greece, Jun. 21-23, 2012. cited
by applicant .
Srinivasan et al., "Digital Microfluidic Lab-on-a-Chip for Protein
Crystallization", The 82nd ACS Colloid and Surface Science
Symposium, 2008. cited by applicant .
Srinivasan et al., "Digital Microfluidics: a novel platform for
multiplexed detection of lysosomal storage diseases for newborn
screening", AACC Oak Ridge Conference Abstracts, Clinical
Chemistry, vol. 54, 2008, 1934. cited by applicant .
Srinivasan et al., "Droplet-based microfluidic lab-on-a-chip for
glucose detection", Analytica Chimica Acta, vol. 507, No. 1, 2004,
145-150. cited by applicant .
Srinivasan et al., "Electrowetting", Chapter 5, Methods in
Bioengineering: Biomicrofabrication and Biomicrofluidics, Ed. J.D.
Zahn, ISBN: 9781596934009, Artech House Publishers, 2010. cited by
applicant .
Srinivasan et al., "Feasibility of a point of care newborn
screening platform for hyperbilirubinemia", APHL Newborn Screening
and Genetic Testing Symposium, San Diego, 2011. cited by applicant
.
Srinivasan et al., "Low cost digital microfluidic platform for
protein crystallization", Enabling Technologies for Structural
Biology, NIGMS Workshop, Bethesda, MD., Mar. 4-6, 2009, J-23. cited
by applicant .
Srinivasan et al., "Protein Stamping for MALDI Mass Spectrometry
Using an Electrowetting-based Microfluidic Platform",
Lab-on-a-Chip: Platforms, Devices, and Applications, Conf. 5591,
SPIE Optics East, Philadelphia, Oct. 25-28, 2004. cited by
applicant .
Srinivasan et al., "Scalable Macromodels for Microelectromechanical
Systems", Technical Proc. 2001 Int. Conf. on Modeling and
Simulation of Microsystems, 2001, 72-75. cited by applicant .
Su et al., "Yield Enhancement of Digital Microfluidics-Based
Biochips Using Space Redundancy and Local Reconfiguration", Proc.
Design, Automation and Test in Europe (DATE) Conf., IEEE, 2005,
1196-1201. cited by applicant .
Sudarsan et al., "Printed circuit technology for fabrication of
plastic based microfluidic devices", Analytical Chemistry vol. 76,
No. 11, Jun. 1, 2004, Previously published on-line, line, May 2004,
3229-3235. cited by applicant .
Thwar et al., "DNA sequencing using digital microfluidics", Poster
42, 41st AACC's Annual Oak Ridge Conference Abstracts, Clinical
Chemistry vol. 55, 2009, 1891. cited by applicant .
Tolun et al., "A Novel Fluorometric Enzyme Analysis Method for
Hunter Syndrome Using Dried Blood Spots", Mol. Genet. Metab., 105,
Issue 3, 2012; doi:10.1016/j.ymgme.2011.12.011, Epub, Dec. 21,
2011, 519-521. cited by applicant .
Tolun et al., "Dried blood spot based enzyme assays for lysosomal
storage disorders", 2011 Tokyo Meeting on Lysosomal Storage Disease
Screening, Tokyo, Aug. 5, 2011. cited by applicant .
Wang et al., "Comparison of enzyme activities for Pompe, Fabry, and
Gaucher diseases on CDC's Quality Control spots between microplate
fluorometry, mass spectrometry, and digital microfluidic
fluorometry", APHL Newborn Screening and Genetic Testing Symposium,
San Diego, 2011. cited by applicant .
Wang et al., "Droplet-based micro oscillating-flow PCR chip", J.
Micromechanics and Microengineering, vol. 15, 2005, 1369-1377.
cited by applicant .
Wang et al., "Efficient in-droplet separation of magnetic particles
for digital microfluidics", Journal of Micromechanics and
Microengineering, vol. 17, 2007, 2148-2156. cited by applicant
.
Weaver, "Application of Magnetic Microspheres for Pyrosequencing on
a Digital Microfluidic Platform", Department of Electrical and
Computer Engineering, Duke University, 2005. cited by applicant
.
Wulff-Burchfield et al., "Microfluidic platform versus conventional
real-time polymerase chain reaction for the detection of Mycoplasma
pneumoniae in respiratory specimens", Diagnostic Microbiology and
Infectious Disease, vol. 67, 2010, 22-29. cited by applicant .
Xu et al., "A Cross-Referencing-Based Droplet Manipulation Method
for High-Throughput and Pin-Constrained Digital Microfluidic
Arrays", Proceedings of conference on Design, Automation and Test
in Europe, Apr. 2007. cited by applicant .
Xu et al., "Automated Design of Pin-Constrained Digital
Microfluidic Biochips Under Droplet-Interference Constraints", ACM
Journal on Emerging Technologies is Computing Systems, vol. 3(3),
2007, 14:1-14:23. cited by applicant .
Xu et al., "Automated solution preparation on a digital
microfluidic lab-on-chip", PSI Bottlenecks Workshop, 2008. cited by
applicant .
Xu et al., "Automated, Accurate and Inexpensive
Solution-Preparation on a Digital Microfluidic Biochip", Proc. IEEE
Biomedical Circuits and Systems Conference (BioCAS), 2008, 301-304.
cited by applicant .
Xu et al., "Defect-Aware Synthesis of Droplet-Based Microfluidic
Biochips", IEEE, 20th International Conference on VLSI Design,
2007. cited by applicant .
Xu et al., "Defect-Tolerant Design and Optimization of a Digital
Microfluidic Biochip for Protein Crystallization", IEEE
Transactions on Computer Aided Design, vol. 29, No. 4, 2010,
552-565. cited by applicant .
Xu et al., "Design and Optimization of a Digital Microfluidic
Biochip for Protein Crystallization", Proc. IEEE/ACM International
Conference on Computer-Aided Design (ICCAD), Nov. 2008, 297-301.
cited by applicant .
Xu et al., "Digital Microfluidic Biochip Design for Protein
Crystallization", IEEE-NIH Life Science Systems and Applications
Workshop, LISA, Bethesda, MD, Nov. 8-9, 2007, 140-143. cited by
applicant .
Xu et al., "Droplet-Trace-Based Array Partitioning and a Pin
Assignment Algorithm for the Automated Design of Digital
Microfluidic Biochips", CODES, 2006, 112-117. cited by applicant
.
Xu et al., "Integrated Droplet Routing in the Synthesis of
Microfluidic Biochips", IEEE, 2007, 948-953. cited by applicant
.
Xu et al., "Parallel Scan-Like Test and Multiple-Defect Diagnosis
for Digital Microfluidic Biochips", IEEE Transactions on Biomedical
Circuits and Systems, vol. 1(2), Jun. 2007, 148-158. cited by
applicant .
Xu et al., "Parallel Scan-Like Testing and Fault Diagnosis
Techniques for Digital Microfluidic Biochips", Proceedings of the
12th IEEE European Test Symposium (ETS), Freiburg, Germany, May
20-24, 2007, 63-68. cited by applicant .
Yang et al., "Manipulation of droplets in microfluidic systems",
Trends in Analytical Chemistry, vol. 29, Feb. 2010, 141-157. cited
by applicant .
Yao et al., "Spot Cooling Using Thermoelectric Microcooler", Proc.
18th Int. Thermoelectric Conf, Baltimore, VA, pp. 256-259, Aug.
1999. cited by applicant .
Yi et al., "Channel-to-droplet extractions for on-chip sample
preparation", Solid-State Sensor, Actuators and Microsystems
Workshop (Hilton Head '06), Hilton Head Island, SC, Jun. 2006,
128-131. cited by applicant .
Yi et al., "Characterization of electrowetting actuation on
addressable single-side coplanar electrodes", Journal of
Micromechanics and Microengineering, vol. 16.,Oct. 2006, 2053-2059.
cited by applicant .
Yi et al., "EWOD Actuation with Electrode-Free Cover Plate", Digest
of Tech. papers, 13th International Conference on Solid-State
Sensors, Actuators and Microsystems (Transducers '05), Seoul,
Korea, Jun. 5-9, 2005, 89-92. cited by applicant .
Yi et al., "Geometric surface modification of nozzles for complete
transfer of liquid drops", Solid-State Sensor, Actuator and
Microsystems Workshop, Hilton Head Island, South Carolina, Jun.
6-10, 2004, 164-167. cited by applicant .
Yi, "Soft Printing of Biological Liquids for Micro-arrays: Concept,
Principle, Fabrication, and Demonstration", Ph.D. dissertation,
UCLA, 2004. cited by applicant .
Yi et al., "Soft Printing of Droplets Digitized by Electrowetting",
Transducers 12th Int'l Conf. on Solid State Sensors, Actuators and
Microsystems, Boston, Jun. 8-12, 2003, 1804-1807. cited by
applicant .
Yi et al., "Soft Printing of Droplets Pre-Metered by
Electrowetting", Sensors and Actuators A: Physical, vol. 114, Jan.
2004, 347-354. cited by applicant .
Zeng et al., "Actuation and Control of Droplets by Using
Electrowetting-on-Dielectric", Chin. Phys. Lett., vol. 21(9), 2004,
1851-1854. cited by applicant .
Zhao et al., "Droplet Manipulation and Microparticle Sampling on
Perforated Microfilter Membranes", J. Micromech. Microeng., vol.
18, 2008, 1-11. cited by applicant .
Zhao et al., "In-droplet particle separation by travelling wave
dielectrophoresis (twDEP) and EWOD", Solid-State Sensor, Actuators
and Microsystems Workshop (Hilton Head '06), Hilton Head Island,
SC, Jun. 2006, 181-184. cited by applicant .
Zhao et al., "Micro air bubble manipulation by electrowetting on
dielectric (EWOD): transporting, splitting, merging and eliminating
of bubbles", Lab on a chip, vol. 7, 2007, First published as an
Advance Article on the web, Dec. 4, 2006, 273-280. cited by
applicant .
Zhao et al., "Microparticle Concentration and Separation
byTraveling-Wave Dielectrophoresis (twDEP) for Digital
Microfluidics", J. Microelectromechanical Systems, vol. 16, No. 6,
Dec. 2007, 1472-1481. cited by applicant .
Zhao et al., "Optimization Techniques for the Synchronization of
Concurrent Fluidic Operations in Pin-Constrained Digital
Microfluidic Biochips", IEEE Transactions on Very Large Scale
Integration (VLSI) Systems, vol. 20, No. 6, Jun. 2012, 1132-1145.
cited by applicant .
Zhao et al., "Synchronization of Concurrently-Implemented Fluidic
Operations in Pin-Constrained Digital Microfluidic Biochips", VLSI
Design, (Best Paper Award), 2010. cited by applicant .
International Search Report and Written Opinion dated Nov. 23, 2012
from PCT International Application No. PCT/US2012/036949. cited by
applicant .
International Preliminary Report on Patentability dated Nov. 12,
2013 from PCT International Application No. PCT/US2012/036949.
cited by applicant .
Dhindsa et al. "Virtual electrowetting channels: electronic liquid
transport with continuous channel functionality" Lab Chip vol. 10,
2010, pp. 832-836. cited by applicant .
Fan et al., "General digital microfluidic platform manipulating
dielectric and conductive droplets by dielectrophoresis and
electrowetting", Lab Chip, 2009, 9:1236-1242. cited by applicant
.
European Search Report dated Oct. 14, 2014 from EP Application No.
12781709. cited by applicant .
Office Action dated Apr. 24, 2015 from U.S. Appl. No. 13/545,716.
cited by applicant .
International Preliminary Report on Patentability dated Mar. 19,
2013 from PCT International Application No. PCT/US2011/051691.
cited by applicant .
International Search Report and Written Opinion dated May 1, 2012
from PCT International Application No. PCT/US2011/051691. cited by
applicant .
Office Action dated Jul. 10, 2015 from U.S. Appl. No. 13/822,990.
cited by applicant .
International Search Report and Written Opinion dated Jul. 9, 2012
from PCT International Application No. PCT/US2011/060714. cited by
applicant .
International Preliminary Report on Patentability dated May 21,
2013 from PCT International Application No. PCT/US2011/060714.
cited by applicant .
Office Action dated Aug. 17, 2015 from U.S. Appl. No. 13/988,190.
cited by applicant .
Ding, "System level architectural optimization of
semi-reconfigurable micro fluidic system", M.S. Thesis, Duke
University Dept of Electrical Engineering, 2000. cited by applicant
.
Gong et al., "Portable digital microfluidics platform with active
but disposable Lab-On-Chip," Micro Electro Mechanical Systems, 17th
IEEE International Conference on (MEMS), Maastricht, Netherlands,
Jan. 25-29, 2004; Piscataway, NJ, IEEE, Jan. 25, 2004, pp. 355-358.
cited by applicant .
Moon, Ph.D. thesis, "Electrowetting-on-dielectric microfluidics:
Modeling, physics, and MALDI application," University of
California, Los Angeles, 2005. cited by applicant .
Pamula et al., "Digital microfluidics for lab-on-a-chip
applications", Emerging CAD challenges for biochip design, design,
automation, and test in Europe, Munich, Germany, 2006. cited by
applicant .
Pamula et al., Microfluidic electrowetting-based droplet mixing,
Proceedings, MEMS Conference Berkeley, Aug. 8-10, 2001. cited by
applicant .
Yi et al., "Microfluidics technology for manipulation and analysis
of biological cells", Analytica Chimica Acta, vol. 560, 2006, 1-23.
cited by applicant .
Office Action dated Nov. 26, 2012 from U.S. Appl. No. 12/527,208.
cited by applicant .
Office Action dated Mar. 26, 2013 from U.S. Appl. No. 12/527,208.
cited by applicant .
International Search Report and Written Opinion dated Jul. 30, 2008
from PCT International Application No. PCT/US2008/054134. cited by
applicant .
International Preliminary Report on Patentability dated Nov. 17,
2009 from PCT International Application No. PCT/US2008/054134.
cited by applicant .
Published abstract from NIH Grant Project No. DK066956-02. cited by
applicant .
Published abstract from NIH Grant Project No. GM072155-02. cited by
applicant .
Office Action dated Jul. 20, 2015 from U.S. Appl. No. 14/338,889.
cited by applicant .
Paik, et al., "Active cooling techniques for integrated circuits",
IEEE Transactions on VLSI, vol. 16, No. 4, 2008, 432-443. cited by
applicant .
Office Action dated Nov. 26, 2012 from related U.S. Pat. No.
8,872,527. cited by applicant .
Office Action dated Mar. 26, 2013 from related U.S. Pat. No.
8,872,527. cited by applicant .
Office Action dated Nov. 6, 2015 from U.S. Appl. No. 13/545,716.
cited by applicant .
Response to Office Action dated Jul. 24, 2015 from U.S. Appl. No.
13/545,716. cited by applicant .
Response to Office Action dated Nov. 17, 2015 from U.S. Appl No.
13/988,190. cited by applicant .
Response to Office Action dated Oct. 8, 2015 from U.S. Appl. No.
13/822,990. cited by applicant .
Response to Office Action dated Feb. 18, 2015 from U.S. Pat. No.
8,872,527. cited by applicant .
Binks, "Wetting: theory and experiment", Current Opinion in
Colloids and Interface Science, vol. 6, No. 1, 17-21, 2001. cited
by applicant .
Chamberlain, et al., "Deletion screening of Duchenne musular
dystrophy locus via multiplex DNA amplification", Nuc. Acid. Res.
16, pp. 11141-11156, 1988. cited by applicant .
Cho, et al., "Concentration and binary separation of micro
particles for droplet-based digital microfluidics", Lab Chip, vol.
7, 490-498, 2007. cited by applicant .
Coltro et al., "Toner and paper-based fabrication techniques for
microfluidic applications", Electrophoresis, vol. 31, 2487-2498,
Jul. 2010. cited by applicant .
Dorfman, et al., "Contamination-Free Continuouse Flow Microfluidic
Polymerase Chain Reaction for Quantitative and Clinical
Applications", Analytical Chemistry 77, 3700-3704, 2005. cited by
applicant .
Fowler, "Labon-on-a-Chip Technology May Present New ESD
Challenges", Electrostatic Discharge (ESD) Journal. Retrieved on
Apr. 18, 2008
from:http://www.esdjournal.com/articles/labchip/Lab.htm., Mar.
2002. cited by applicant .
Gijs, Mam, "Magnetic bead handling on-chip:new opportunities for
analytical applications", Microfluidics and Nanofluidics, vol. 1,
22-40, Oct. 2, 2004. cited by applicant .
Huang, et al., "MEMS-based sample preparation for molecular
diagnostics", Analytical and Bioanalytical Chemistry, vol. 372,
49-65, 2002. cited by applicant .
Jones, et al., "Dielectrophoretic liquid actuation and nanodroplet
formation", J. Appl. Phys., vol. 89, No. 2, 1441-1448, Jan. 2001.
cited by applicant .
Kim, et al., "Electrowetting on paper for electronic paper
display", ACS Applied Materials & Interfaces, vol. 2,
3318-3323, Nov. 2010. cited by applicant .
Margulies, et al., "Genome sequencing in microfabricated
high-density picolitre reactors", Nature, vol. 437, 376-380 and
Supplemental Materials, 2005. cited by applicant .
Park, et al., "Single-sided continuous optoelectrowetting (SCOEW)
droplet manipulation with light patterns", Lab on a chip, vol. 10,
1655-1661, Jul. 2010. cited by applicant .
Pinho, et al., "Haemopoietic progenitors in the adult mouse
omentum: permanent production of B lymphocytes and monocytes", Cell
Tissue Res., vol. 319, No. 1, 91-102, Jan. 2005. cited by applicant
.
Poliski, Making materials fit the future: accommodating relentless
technological requirements means researchers must recreate and
reconfigure materials, frequently challenging established laws of
physics, while keeping an eye on Moore's Law, R&D Magazine
Conference, Dec. 2001. cited by applicant .
Raj, et al., Composite Dielectrics and Surfactants for Low Voltage
Electrowetting Devices, University/Government/Industry Micro/Nano
Symposium, vol. 17, 187-190, Jul. 13-16, 2008. cited by applicant
.
Russom, et al., "Pyrosequencing in a Microfluidic Flow-Through
Device", Anal. Chem. vol. 77, 7505-7511, 2005. cited by applicant
.
Schwartz, et al., "Dielectrophoretic approaches to sample
preparation and analysis", The University of Texas, Dissertation,
Dec. 2001. cited by applicant .
Shah, et al., "EWOD-driven droplet microfluidic device integrated
with optoelectronic tweezers as an automated platform for cellular
isolation and analysis", Lab on a Chip, vol. 9, 1732-1739, Jun.
2009. cited by applicant .
Tsuchiya, et al., "On-chip polymerase chain reaction microdevice
employing a magnetic droplet-manipulation system", Sensors and
Actuators B, vol. 130, 583-588, Oct. 18, 2007. cited by applicant
.
Welch, et al., "Picoliter DNA sequencing chemistry on an
electrowetting-based digital microfluidic platform", Biotechnology
Journal, vol. 6, 165-176, Feb. 2011. cited by applicant .
Wheeler, et al., "Electrowetting-Based Microfluidics for Analysis
of Peptides and Proteins by Matrix-Assisted Laser
Desportion/Ionization Mass Spectrometry", Anal. Chem. 76,
4833-4838, 2004. cited by applicant .
Yl et al., "Microfluidics technology for manipulation and analysis
of biological cells", Analytica Chimica Acta, vol. 560, 1-23, 2006.
cited by applicant.
|
Primary Examiner: Dieterle; Jennifer
Attorney, Agent or Firm: Ward and Smith, P.A. Simmons; Ryan
K.
Parent Case Text
1 RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser.
No. 14/116,553, filed Mar. 12, 2014, the application of which is a
35 U.S.C. 371 U.S. national phase entry of International
Application No. PCT/US2012/036949 having an international filing
date of May 8, 2012, the application of which claims the benefit of
U.S. Provisional Application No. 61/483,827, filed May 9, 2011, the
content of each of the aforementioned applications is herein
incorporated by reference in its entirety.
Claims
The invention claimed is:
1. A method, comprising: a. receiving an output voltage signal
produced by a power supply; b. superimposing an excitation signal
onto the output voltage signal to produce a superimposed signal; c.
connecting the superimposed signal to one or more certain
electrowetting electrodes in a droplet actuator, wherein the
droplet actuator comprises: i. a first substrate and a second
substrate separated to form a gap therebetween; ii. electrowetting
electrodes arranged on a gap facing surface of at least one of the
first substrate and second substrate; and iii. a filler fluid in
the gap; d. suppressing the output voltage signal when detecting an
impedance of the one or more certain electrowetting electrodes; and
e. measuring the impedance of the one or more certain
electrowetting electrodes produced by the excitation signal,
wherein the impedance indicates presence of liquid at the one or
more certain electrowetting electrodes.
2. The method of claim 1, wherein the filler fluid comprises an oil
filler fluid.
3. The method of claim 2, wherein the oil filler fluid comprises a
silicone oil.
4. The method of claim 1, wherein superimposing the excitation
signal comprises adding the excitation signal to the output voltage
signal.
5. The method of claim 1, wherein suppressing the output voltage
signal comprises stopping the output voltage signal.
6. The method of claim 1, wherein suppressing the output voltage
signal comprises disabling a switching action of the power
supply.
7. The method of claim 1, wherein suppressing the output voltage
signal comprises disabling the power supply.
8. The method of claim 1, further comprising receiving a
suppression signal to suppress the output voltage signal from the
power supply.
9. The method of claim 1, further comprising determining a
saturation of the impedance.
10. The method of claim 1, further comprising: a. injecting the
liquid into the gap of the droplet actuator; and b. stopping
injection when the impedance indicates the liquid has flowed to the
one or more certain electrowetting electrodes.
11. The method of claim 1, further comprising: a. injecting the
liquid into a reservoir in the droplet actuator; and b. stopping
injection when the impedance indicates the liquid has flowed to the
one or more certain electrowetting electrodes.
12. The method of claim 1, further comprising: a. injecting the
liquid to fill a reservoir in the droplet actuator; and b. stopping
injection when the impedance indicates the liquid has flowed from
the reservoir to the one or more certain electrowetting
electrodes.
13. The method of claim 1, further comprising: a. establishing a
fluid path in the droplet actuator from an input port to a
reservoir to the one or more certain electrowetting electrodes; b.
injecting the liquid through the input port to fill the reservoir;
and c. stopping injection when the impedance indicates the liquid
has flowed to the one or more certain electrowetting
electrodes.
14. The method of claim 1, further comprising: a. arranging an
input port outside a boundary of a reservoir in the droplet
actuator; b. forming a fluid path from the input port to the
reservoir to the one or more certain electrowetting electrodes; c.
injecting the liquid through the input port to fill the reservoir;
and d. stopping injection when the impedance indicates the liquid
has flowed to the one or more certain electrowetting
electrodes.
15. A method, comprising: a. generating an output voltage by a
power supply; b. storing charge produced by the output voltage; c.
superimposing an excitation signal onto the output voltage to
produce a superimposed signal; d. connecting the superimposed
signal to one or more certain electrowetting electrodes in a
droplet actuator, wherein the droplet actuator comprises: i. a
first substrate and a second substrate separated to form a gap
therebetween; ii. electrowetting electrodes arranged on a gap
facing surface of at least one of the first substrate and second
substrate; and iii. a filler fluid in the gap; e. suppressing the
output voltage from the power supply when detecting an impedance at
the one or more certain electrowetting electrodes; f. supplying the
charge to the droplet actuator to activate the one or more certain
electrowetting electrodes during the impedance; and g. measuring
the impedance produced by the excitation signal while the output
voltage is suppressed, wherein the impedance indicates presence of
liquid at the one or more certain electrowetting electrodes.
16. The method of claim 15, wherein the filler fluid comprises an
oil filler fluid.
17. The method of claim 16, wherein the oil filler fluid comprises
a silicone oil.
18. The method of claim 15, wherein superimposing the excitation
signal comprises adding the excitation signal to the output
voltage.
19. The method of claim 15, wherein suppressing the output voltage
comprises at least one of stopping the output voltage generated by
the power supply, disabling a switching action of the power supply,
and disabling the power supply during the impedance
measurement.
20. The method of claim 15, further comprising activating a
suppression signal to suppress the output voltage generated by the
power supply.
21. The method of claim 20, further comprising deactivating the
suppression signal to resume the output voltage generated by the
power supply.
22. The method of claim 15, further comprising charging a capacitor
to store the charge.
23. The method of claim 15, further comprising determining the
impedance is saturated.
24. The method of claim 15, further comprising: a. injecting the
liquid into the droplet actuator; and b. stopping injection when
the impedance indicates the liquid has flowed to the one or more
certain electrowetting electrodes.
25. The method of claim 15, further comprising: a. injecting the
liquid into the gap in the droplet actuator; and b. stopping
injection into the gap when the impedance indicates the liquid has
flowed to the one or more certain electrowetting electrodes.
26. The method of claim 15, further comprising: a. injecting the
liquid into a reservoir in the droplet actuator; and b. stopping
injection into the reservoir when the impedance indicates the
liquid has flowed to the one or more certain electrowetting
electrodes.
27. The method of claim 15, further comprising: a. establishing a
fluid path in the droplet actuator from an input port to a
reservoir to the one or more certain electrowetting electrodes; b.
injecting the liquid through the input port to fill the reservoir;
and c. stopping injection when the impedance indicates the liquid
has flowed to the one or more certain electrowetting
electrodes.
28. The method of claim 1, further comprising: a. arranging an
input port outside a boundary of a reservoir in the droplet
actuator; b. forming a fluid path from the input port to the
reservoir to the one or more certain electrowetting electrodes; c.
injecting the liquid through the input port to fill the reservoir;
and d. stopping injection when the impedance indicates the liquid
has flowed to the one or more certain electrowetting
electrodes.
29. A system, comprising: a. a controller; b. memory; and c. the
controller configured to: i. receive an output voltage signal; ii.
superimpose an excitation signal onto the output voltage signal to
produce a superimposed signal; iii. connect the superimposed signal
to one or more certain electrowetting electrodes in a droplet
actuator; wherein the droplet actuator comprises: a first substrate
and a second substrate separated to form a gap therebetween;
electrowetting electrodes arranged on a gap facing surface of at
least one of the first substrate and second substrate; and a filler
fluid in the gap; iv. suppress the output voltage signal when
detecting an impedance of the one or more certain electrowetting
electrodes; and v. measure the impedance of the one or more certain
electrowetting electrodes produced by the excitation signal,
wherein the impedance indicates presence of liquid at the one or
more certain electrowetting electrodes.
30. The method of claim 29, wherein the filler fluid comprises an
oil filler fluid.
31. The method of claim 30, wherein the oil filler fluid comprises
a silicone oil.
32. The system of claim 29, wherein the controller is further
configured to at least one of add the excitation signal to the
output voltage signal, stop the output voltage signal, disable a
switching action of the power supply, and disable the power
supply.
33. The system of claim 29, wherein the controller is further
configured to determine a saturation of the impedance.
34. The system of claim 29, wherein the controller is further
configured to: a. cause injection of the liquid into the droplet
actuator; and b. stop the injection when the impedance indicates
the liquid has flowed to the one or more certain electrowetting
electrodes.
35. The system of claim 29, wherein the controller is further
configured to: a. cause injection of the liquid into the gap in the
droplet actuator; and b. stop the injection when the impedance
indicates the liquid has flowed to the one or more certain
electrowetting electrodes.
36. The system of claim 29, wherein the controller is further
configured to: a. cause injection of the liquid into a reservoir in
the droplet actuator; and b. stop the injection when the impedance
indicates the liquid has flowed to the one or more certain
electrowetting electrodes.
37. The system of claim 29, wherein the controller is further
configured to: a. cause the injection of the liquid to fill a
reservoir in the droplet actuator; and b. stop the injection when
the impedance indicates the liquid has flowed from the reservoir to
the one or more certain electrowetting electrodes.
38. The system of claim 29, wherein the controller is further
configured to: a. cause injection of the liquid into an input port
of a reservoir in the droplet actuator; and b. stop the injection
when the impedance indicates the liquid has flowed along a fluid
path from the reservoir to the one or more certain electrowetting
electrodes.
39. A non-transitory computer readable medium comprising: a.
generating an output voltage by a power supply; b. storing charge
produced by the output voltage; c. superimposing an excitation
signal onto the output voltage to produce a superimposed signal; d.
connecting the superimposed signal to one or more certain
electrowetting electrodes in a droplet actuator, wherein the
droplet actuator comprises: i. a first substrate and a second
substrate separated to form a gap therebetween; ii. electrowetting
electrodes arranged on a gap facing surface of at least one of the
first substrate and second substrate; and iii. a filler fluid in
the gap; e. suppressing the output voltage from the power supply
when detecting an impedance at the one or more certain
electrowetting electrodes; f. supplying the charge to the droplet
actuator to activate the one or more certain electrowetting
electrodes during the impedance; and g. measuring the impedance
produced by the excitation signal while the output voltage is
suppressed, wherein the impedance indicates presence of liquid at
the one or more certain electrowetting electrodes.
40. The method of claim 39, wherein the filler fluid comprises an
oil filler fluid.
41. The method of claim 40, wherein the oil filler fluid comprises
a silicone oil.
42. The non-transitory computer readable medium of claim 39,
further comprising instructions for at least one of adding the
excitation signal to the output voltage, stopping the output
voltage generated by the power supply, disabling a switching action
of the power supply, and disabling the power supply during the
impedance measurement.
43. The non-transitory computer readable medium of claim 39,
further comprising instructions for activating a suppression signal
to suppress the output voltage generated by the power supply.
44. The non-transitory computer readable medium of claim 43,
further comprising instructions for deactivating the suppression
signal to resume the output voltage generated by the power
supply.
45. The non-transitory computer readable medium of claim 39,
further comprising instructions for charging a capacitor to store
the charge.
46. The non-transitory computer readable medium of claim 39,
further comprising instructions for determining the impedance is
saturated.
47. The non-transitory computer readable medium of claim 39,
further comprising instructions for: a. injecting the liquid into
the droplet actuator; and b. stopping injection when the impedance
indicates the liquid has flowed to the one or more certain
electrowetting electrodes.
48. The non-transitory computer readable medium of claim 39,
further comprising instructions for: a. injecting the liquid into a
gap in the droplet actuator; and b. stopping injection into the gap
when the impedance indicates the liquid has flowed to the one or
more certain electrowetting electrodes.
49. The non-transitory computer readable medium of claim 39,
further comprising instructions for: a. injecting the liquid into a
reservoir in the droplet actuator; and b. stopping injection into
the reservoir when the impedance indicates the liquid has flowed to
the one or more certain electrowetting electrodes.
50. The non-transitory computer readable medium of claim 39,
further comprising instructions for: a. injecting the liquid
through an input port to fill a reservoir in the droplet actuator;
b. stopping injection when the impedance indicates the liquid has
flowed to the one or more certain electrowetting electrodes.
51. The non-transitory computer readable medium of claim 39,
further comprising instructions for: a. injecting the liquid into
an input port of a reservoir in the droplet actuator; and b.
stopping injection when the impedance indicates the liquid has
flowed along a fluid path from the reservoir to the one or more
certain electrowetting electrodes.
Description
2 BACKGROUND
A droplet actuator typically includes one or more substrates
configured to form a surface or gap for conducting droplet
operations. The one or more substrates establish a droplet
operations surface or gap for conducting droplet operations and may
also include electrodes arrange to conduct the droplet operations.
The droplet operations substrate or the gap between the substrates
may be coated or filled with a filler fluid that is immiscible with
the liquid that forms the droplets. It may be beneficial to
determine and/or verify the presence or absence of liquid at
certain electrodes of a droplet actuator, such as at droplet
operations electrodes and reservoir electrodes. Therefore, there is
a need for methods of microfluidic feedback in droplet
actuators.
3 BRIEF DESCRIPTION OF THE INVENTION
In one embodiment, the invention provides a method, which includes
receiving an output voltage signal produced by a power supply,
superimposing an excitation signal onto the output voltage signal
to produce a superimposed signal, connecting the superimposed
signal to an electrode in a droplet actuator, suppressing the
output voltage signal when detecting an impedance of the electrode,
and measuring the impedance of the electrode produced by the
excitation signal, wherein the impedance indicates presence of
liquid at the electrode. In some cases, superimposing the
excitation signal includes adding the excitation signal to the
output voltage signal. In certain embodiments suppressing the
output voltage signal includes stopping the output voltage signal.
In certain embodiments suppressing the output voltage signal
includes disabling a switching action of the power supply. In
certain embodiments suppressing the output voltage signal includes
disabling the power supply. In certain embodiments the method
includes receiving a suppression signal to suppress the output
voltage signal from the power supply. In certain embodiments the
method includes determining a saturation of the impedance. In
certain embodiments the method includes: injecting the liquid into
the droplet actuator, and stopping injection when the impedance
indicates the liquid has flowed to the electrode. In certain
embodiments the method includes: injecting the liquid into a gap in
the droplet actuator, and stopping injection when the impedance
indicates the liquid has flowed to the electrode. In certain
embodiments the method includes: injecting the liquid into a
reservoir in the droplet actuator, and stopping injection when the
impedance indicates the liquid has flowed to the electrode. In
certain embodiments the method includes: injecting the liquid to
fill a reservoir in the droplet actuator, and stopping injection
when the impedance indicates the liquid has flowed from the
reservoir to the electrode. In certain embodiments the method
includes: establishing a fluid path in the droplet actuator from an
input port to a reservoir to the electrode, injecting the liquid
through the input port to fill the reservoir, and stopping
injection when the impedance indicates the liquid has flowed to the
electrode. In certain embodiments the method includes: arranging an
input port outside a boundary of a reservoir in the droplet
actuator, forming a fluid path from the input port to the reservoir
to the electrode, injecting the liquid through the input port to
fill the reservoir, and stopping injection when the impedance
indicates the liquid has flowed to the electrode. In another
embodiment, the method includes generating an output voltage by a
power supply, storing charge produced by the output voltage,
superimposing an excitation signal onto the output voltage to
produce a superimposed signal, connecting the superimposed signal
to an electrode in a droplet actuator, suppressing the output
voltage from the power supply when detecting an impedance at the
electrode, supplying the charge to the droplet actuator to activate
the electrode during the impedance, and measuring the impedance
produced by the excitation signal while the output voltage is
suppressed, wherein the impedance indicates presence of liquid at
the electrode. In certain embodiments superimposing the excitation
signal includes adding the excitation signal to the output voltage.
In certain embodiments suppressing the output voltage includes at
least one of stopping the output voltage generated by the power
supply, disabling a switching action of the power supply, and
disabling the power supply during the impedance measurement. In
certain embodiments the invention includes activating a suppression
signal to suppress the output voltage generated by the power
supply. In certain embodiments the method includes deactivating the
suppression signal to resume the output voltage generated by the
power supply. In certain embodiments the method includes charging a
capacitor to store the charge. In certain embodiments the method
includes determining whether the impedance is saturated. In certain
embodiments the method includes: injecting the liquid into the
droplet actuator, and stopping injection when the impedance
indicates the liquid has flowed to the electrode. In certain
embodiments the method includes: injecting the liquid into a gap in
the droplet actuator, and stopping injection into the gap when the
impedance indicates the liquid has flowed to the electrode. In
certain embodiments the method includes: injecting the liquid into
a reservoir in the droplet actuator, and stopping injection into
the reservoir when the impedance indicates the liquid has flowed to
the electrode. In certain embodiments the method includes:
establishing a fluid path in the droplet actuator from an input
port to a reservoir to the electrode, injecting the liquid through
the input port to fill the reservoir, and stopping injection when
the impedance indicates the liquid has flowed to the electrode. In
certain embodiments the method includes: arranging an input port
outside a boundary of a reservoir in the droplet actuator, forming
a fluid path from the input port to the reservoir to the electrode,
injecting the liquid through the input port to fill the reservoir,
and stopping injection when the impedance indicates the liquid has
flowed to the electrode.
In another embodiment, the invention provides a system, comprising:
a processor, memory, and code stored in the memory that when
executed cause the processor at least to: receive an output voltage
signal, superimpose an excitation signal onto the output voltage
signal to produce a superimposed signal, connect the superimposed
signal to an electrode in a droplet actuator, suppress the output
voltage signal when detecting an impedance of the electrode, and
measure the impedance of the electrode produced by the excitation
signal, wherein the impedance indicates presence of liquid at the
electrode. In some cases, the code further causes the processor to
at least one of add the excitation signal to the output voltage
signal, stop the output voltage signal, disable a switching action
of the power supply, and disable the power supply. In some cases,
the code further causes the processor to determine a saturation of
the impedance. In some cases, the code further causes the processor
to: cause injection of the liquid into the droplet actuator, and
stop the injection when the impedance indicates the liquid has
flowed to the electrode. In some cases, the code further causes the
processor to: cause injection of the liquid into a gap in the
droplet actuator, and stop the injection when the impedance
indicates the liquid has flowed to the electrode. In some cases,
the code further causes the processor to: cause injection of the
liquid into a reservoir in the droplet actuator, and stop the
injection when the impedance indicates the liquid has flowed to the
electrode. In some cases, the code further causes the processor to:
cause the injection of the liquid to fill a reservoir in the
droplet actuator, and stop the injection when the impedance
indicates the liquid has flowed from the reservoir to the
electrode. In some cases, the code further causes the processor to:
cause injection of the liquid into an input port of a reservoir in
the droplet actuator, and stop the injection when the impedance
indicates the liquid has flowed along a fluid path from the
reservoir to the electrode. The code may be cause the operation of
any of the methods of the invention.
The invention provides a computer readable medium storing processor
executable instructions for performing a method, the method
comprising: generating an output voltage by a power supply, storing
charge produced by the output voltage, superimposing an excitation
signal onto the output voltage to produce a superimposed signal,
connecting the superimposed signal to an electrode in a droplet
actuator, suppressing the output voltage from the power supply when
detecting an impedance at the electrode, supplying the charge to
the droplet actuator to activate the electrode during the
impedance, and measuring the impedance produced by the excitation
signal while the output voltage is suppressed, wherein the
impedance indicates presence of liquid at the electrode. In some
cases, the computer readable medium includes instructions for at
least one of adding the excitation signal to the output voltage,
stopping the output voltage generated by the power supply,
disabling a switching action of the power supply, and disabling the
power supply during the impedance measurement. In some cases, the
computer readable medium includes instructions for activating a
suppression signal to suppress the output voltage generated by the
power supply. In some cases, the computer readable medium includes
instructions for deactivating the suppression signal to resume the
output voltage generated by the power supply. In some cases, the
computer readable medium includes instructions for charging a
capacitor to store the charge. In some cases, the computer readable
medium includes instructions for determining the impedance is
saturated. In some cases, the computer readable medium includes
instructions for: injecting the liquid into the droplet actuator,
and stopping injection when the impedance indicates the liquid has
flowed to the electrode. In some cases, the computer readable
medium includes instructions for: injecting the liquid into a gap
in the droplet actuator, and stopping injection into the gap when
the impedance indicates the liquid has flowed to the electrode. In
some cases, the computer readable medium includes instructions for:
injecting the liquid into a reservoir in the droplet actuator, and
stopping injection into the reservoir when the impedance indicates
the liquid has flowed to the electrode. In some cases, the computer
readable medium includes instructions for: injecting the liquid
through an input port to fill a reservoir in the droplet actuator,
stopping injection when the impedance indicates the liquid has
flowed to the electrode. In some cases, the computer readable
medium includes instructions for: injecting the liquid into an
input port of a reservoir in the droplet actuator, and stopping
injection when the impedance indicates the liquid has flowed along
a fluid path from the reservoir to the electrode.
4 DEFINITIONS
As used herein, the following terms have the meanings
indicated.
"Activate," with reference to one or more electrodes, means
affecting a change in the electrical state of the one or more
electrodes which, in the presence of a droplet, results in a
droplet operation. Activation of an electrode can be accomplished
using alternating or direct current. Any suitable voltage may be
used. For example, an electrode may be activated using a voltage
which is greater than about 150 V, or greater than about 200 V, or
greater than about 250 V, or from about 275 V to about 375 V, or
about 300 V. Where alternating current is used, any suitable
frequency may be employed. For example, an electrode may be
activated using alternating current having a frequency from about 1
Hz to about 100 Hz, or from about 10 Hz to about 60 Hz, or from
about 20 Hz to about 40 Hz, or about 30 Hz. Droplet operations and
other droplet control electrodes of the invention may be
activated.
"Bead," with respect to beads on a droplet actuator, means any bead
or particle that is capable of interacting with a droplet on or in
proximity with a droplet actuator. Beads may be any of a wide
variety of shapes, such as spherical, generally spherical, egg
shaped, disc shaped, cubical, amorphous and other three dimensional
shapes. The bead may, for example, be capable of being subjected to
a droplet operation in a droplet on a droplet actuator or otherwise
configured with respect to a droplet actuator in a manner which
permits a droplet on the droplet actuator to be brought into
contact with the bead on the droplet actuator and/or off the
droplet actuator. Beads may be provided in a droplet, in a droplet
operations gap, or on a droplet operations surface. Beads may be
provided in a reservoir that is external to a droplet operations
gap or situated apart from a droplet operations surface, and the
reservoir may be associated with a flow path that permits a droplet
including the beads to be brought into a droplet operations gap or
into contact with a droplet operations surface. Beads may be
manufactured using a wide variety of materials, including for
example, resins, and polymers. The beads may be any suitable size,
including for example, microbeads, microparticles, nanobeads and
nanoparticles. In some cases, beads are magnetically responsive; in
other cases beads are not significantly magnetically responsive.
For magnetically responsive beads, the magnetically responsive
material may constitute substantially all of a bead, a portion of a
bead, or only one component of a bead. The remainder of the bead
may include, among other things, polymeric material, coatings, and
moieties which permit attachment of an assay reagent Examples of
suitable beads include flow cytometry microbeads, polystyrene
microparticles and nanoparticles, functionalized polystyrene
microparticles and nanoparticles, coated polystyrene microparticles
and nanoparticles, silica microbeads, fluorescent microspheres and
nanospheres, functionalized fluorescent microspheres and
nanospheres, coated fluorescent microspheres and nanospheres, color
dyed microparticles and nanoparticles, magnetic microparticles and
nanoparticles, superparamagnetic microparticles and nanoparticles
(e.g., DYNABEADS.RTM. particles, available from Invitrogen Group,
Carlsbad, Calif.), fluorescent microparticles and nanoparticles,
coated magnetic microparticles and nanoparticles, ferromagnetic
microparticles and nanoparticles, coated ferromagnetic
microparticles and nanoparticles, and those described in U.S.
Patent Publication Nos. 20050260686, entitled "Multiplex flow
assays preferably with magnetic particles as solid phase,"
published on Nov. 24, 2005; 20030132538, entitled "Encapsulation of
discrete quanta of fluorescent particles," published on Jul. 17,
2003; 20050118574, entitled "Multiplexed Analysis of Clinical
Specimens Apparatus and Method," published on Jun. 2, 2005;
20050277197. Entitled "Microparticles with Multiple Fluorescent
Signals and Methods of Using Same," published on Dec. 15, 2005;
20060159962, entitled "Magnetic Microspheres for use in
Fluorescence-based Applications," published on Jul. 20, 2006; the
entire disclosures of which are incorporated herein by reference
for their teaching concerning beads and magnetically responsive
materials and beads. Beads may be pre-coupled with a biomolecule or
other substance that is able to bind to and form a complex with a
biomolecule. Beads may be pre-coupled with an antibody, protein or
antigen, DNA/RNA probe or any other molecule with an affinity for a
desired target. Examples of droplet actuator techniques for
immobilizing magnetically responsive beads and/or non-magnetically
responsive beads and/or conducting droplet operations protocols
using beads are described in U.S. patent application Ser. No.
11/639,566, entitled "Droplet-Based Particle Sorting," filed on
Dec. 15, 2006; U.S. Patent Application No. 61/039,183, entitled
"Multiplexing Bead Detection in a Single Droplet," filed on Mar.
25, 2008; U.S. Patent Application No. 61/047,789, entitled "Droplet
Actuator Devices and Droplet Operations Using Beads," filed on Apr.
25, 2008; U.S. Patent Application No. 61/086,183, entitled "Droplet
Actuator Devices and Methods for Manipulating Beads," filed on Aug.
5, 2008; International Patent Application No. PCT/US2008/053545,
entitled "Droplet Actuator Devices and Methods Employing Magnetic
Beads," filed on Feb. 11, 2008: International Patent Application
No. PCT/US2008/058018, entitled "Bead-based Multiplexed Analytical
Methods and Instrumentation," filed on Mar. 24, 2008; International
Patent Application No. PCT/US2008/058047, "Bead Sorting on a
Droplet Actuator," filed on Mar. 23, 2008; and International Patent
Application No. PCT/US2006/047486, entitled "Droplet-based
Biochemistry," filed on Dec. 11, 2006; the entire disclosures of
which are incorporated herein by reference. Bead characteristics
may be employed in the multiplexing aspects of the invention.
Examples of beads having characteristics suitable for multiplexing,
as well as methods of detecting and analyzing signals emitted from
such beads, may be found in U.S. Patent Publication No.
20080305481, entitled "Systems and Methods for Multiplex Analysis
of PCR in Real Time," published on Dec. 11, 2008; U.S. Patent
Publication No. 20080151240, "Methods and Systems for Dynamic Range
Expansion," published on Jun. 26, 2008; U.S. Patent Publication No.
20070207513, entitled "Methods, Products, and Kits for Identifying
an Analyte in a Sample," published on Sep. 6, 2007; U.S. Patent
Publication No. 20070064990, entitled "Methods and Systems for
Image Data Processing," published on Mar. 22, 2007; U.S. Patent
Publication No. 20060159962, entitled "Magnetic Microspheres for
use in Fluorescence-based Applications," published on Jul. 20,
2006; U.S. Patent Publication No. 20050277197, entitled
"Microparticles with Multiple Fluorescent Signals and Methods of
Using Same," published on Dec. 15, 2005; and U.S. Patent
Publication No. 20050118574, entitled "Multiplexed Analysis of
Clinical Specimens Apparatus and Method," published on Jun. 2,
2005.
"Droplet" means a volume of liquid on a droplet actuator.
Typically, a droplet is at least partially bounded by a filler
fluid. For example, a droplet may be completely surrounded by a
filler fluid or may be bounded by filler fluid and one or more
surfaces of the droplet actuator. As another example, a droplet may
be bounded by filler fluid, one or more surfaces of the droplet
actuator, and/or the atmosphere. As yet another example, a droplet
may be bounded by filler fluid and the atmosphere. Droplets may,
for example, be aqueous or non-aqueous or may be mixtures or
emulsions including aqueous and non-aqueous components. Droplets
may take a wide variety of shapes; nonlimiting examples include
generally disc shaped, slug shaped, truncated sphere, ellipsoid,
spherical, partially compressed sphere, hemispherical, ovoid,
cylindrical, combinations of such shapes, and various shapes formed
during droplet operations, such as merging or splitting or formed
as a result of contact of such shapes with one or more surfaces of
a droplet actuator. For examples of droplet fluids that may be
subjected to droplet operations using the approach of the
invention, see International Patent Application No. PCT/US
06/47486, entitled, "Droplet-Based Biochemistry," filed on Dec. 11,
2006. In various embodiments, a droplet may include a biological
sample, such as whole blood, lymphatic fluid, serum, plasma, sweat,
tear, saliva, sputum, cerebrospinal fluid, amniotic fluid, seminal
fluid, vaginal excretion, serous fluid, synovial fluid, pericardial
fluid, peritoneal fluid, pleural fluid, transudates, exudates,
cystic fluid, bile, urine, gastric fluid, intestinal fluid, fecal
samples, liquids containing single or multiple cells, liquids
containing organelles, fluidized tissues, fluidized organisms,
liquids containing multi-celled organisms, biological swabs and
biological washes. Moreover, a droplet may include a reagent, such
as water, deionized water, saline solutions, acidic solutions,
basic solutions, detergent solutions and/or buffers. Other examples
of droplet contents include reagents, such as a reagent for a
biochemical protocol, such as a nucleic acid amplification
protocol, an affinity-based assay protocol, an enzymatic assay
protocol, a sequencing protocol, and/or a protocol for analyses of
biological fluids. A droplet may include one or more beads.
"Droplet Actuator" means a device for manipulating droplets. For
examples of droplet actuators, see Pamula et al., U.S. Pat. No.
6,911,132, entitled "Apparatus for Manipulating Droplets by
Electrowetting-Based Techniques," issued on Jun. 28, 2005; Pamula
et al., U.S. patent application Ser. No. 11/343,284, entitled
"Apparatuses and Methods for Manipulating Droplets on a Printed
Circuit Board," filed on filed on Jan. 30, 2006; Pollack et al.,
International Patent Application No. PCT/US2006/047486, entitled
"Droplet-Based Biochemistry," filed on Dec. 11, 2006; Shenderov,
U.S. Pat. No. 6,773,566, entitled "Electrostatic Actuators for
Microfluidics and Methods for Using Same," issued on Aug. 10, 2004
and U.S. Pat. No. 6,565,727, entitled "Actuators for Microfluidics
Without Moving Parts," issued on Jan. 24, 2000; Kim and/or Shah et
al., U.S. patent application Ser. No. 10/343,261, entitled
"Electrowetting-driven Micropumping," filed on Jan. 27, 2003, Ser.
No. 11/275,668, entitled "Method and Apparatus for Promoting the
Complete Transfer of Liquid Drops from a Nozzle," filed on Jan. 23,
2006, Ser. No. 11/460,188, entitled "Small Object Moving on Printed
Circuit Board," filed on Jan. 23, 2006, Ser. No. 12/465,935,
entitled "Method for Using Magnetic Particles in Droplet
Microfluidics," filed on May 14, 2009, and Ser. No. 12/513,157,
entitled "Method and Apparatus for Real-time Feedback Control of
Electrical Manipulation of Droplets on Chip," filed on Apr. 30,
2009; Velev, U.S. Pat. No. 7,547,380, entitled "Droplet
Transportation Devices and Methods Having a Fluid Surface," issued
on Jun. 16, 2009; Sterling et al., U.S. Pat. No. 7,163,612,
entitled "Method, Apparatus and Article for Microfluidic Control
via Electrowetting, for Chemical, Biochemical and Biological Assays
and the Like." issued on Jan. 16, 2007; Becker and Gascoyne et al.,
U.S. Pat. No. 7,641,779, entitled "Method and Apparatus for
Programmable fluidic Processing," issued on Jan. 5, 2010, and U.S.
Pat. No. 6,977,033, entitled "Method and Apparatus for Programmable
fluidic Processing," issued on Dec. 20, 2005; Decre et al., U.S.
Pat. No. 7,328,979, entitled "System for Manipulation of a Body of
Fluid," issued on Feb. 12, 2008; Yamakawa et al., U.S. Patent Pub.
No. 20060039823, entitled "Chemical Analysis Apparatus," published
on Feb. 23, 2006; Wu, International Patent Pub. No. WO/2009/003184,
entitled "Digital Microfluidics Based Apparatus for Heat-exchanging
Chemical Processes," published on Dec. 31, 2008; Fouillet et al.,
U.S. Patent Pub. No. 20090192044, entitled "Electrode Addressing
Method," published on Jul. 30, 2009; Fouillet et al., U.S. Pat. No.
7,052,244, entitled "Device for Displacement of Small Liquid
Volumes Along a Micro-catenary Line by Electrostatic Forces,"
issued on May 30, 2006; Marchand et al., U.S. Patent Pub. No.
20080124252, entitled "Droplet Microreactor," published on May 29,
2008; Adachi et al., U.S. Patent Pub. No. 20090321262, entitled
"Liquid Transfer Device," published on Dec. 31, 2009; Roux et al.,
U.S. Patent Pub. No. 20050179746, entitled "Device for Controlling
the Displacement of a Drop Between two or Several Solid
Substrates," published on Aug. 18, 2005; Dhindsa et al., "Virtual
Electrowetting Channels: Electronic Liquid Transport with
Continuous Channel Functionality," Lab Chip, 10:832-836 (2010); the
entire disclosures of which are incorporated herein by reference,
along with their priority documents. Certain droplet actuators will
include one or more substrates arranged with a droplet operations
gap therebetween and electrodes associated with (e.g., layered on,
attached to, and/or embedded in) the one or more substrates and
arranged to conduct one or more droplet operations. For example,
certain droplet actuators will include a base (or bottom)
substrate, droplet operations electrodes associated with the
substrate, one or more dielectric layers atop the substrate and/or
electrodes, and optionally one or more hydrophobic layers atop the
substrate, dielectric layers and/or the electrodes forming a
droplet operations surface. A top substrate may also be provided,
which is separated from the droplet operations surface by a gap,
commonly referred to as a droplet operations gap. Various electrode
arrangements on the top and/or bottom substrates are discussed in
the above-referenced patents and applications and certain novel
electrode arrangements are discussed in the description of the
invention. During droplet operations it is preferred that droplets
remain in continuous contact, frequent contact or intermittent
contact with a ground or reference electrode. A ground or reference
electrode may be associated with the top substrate facing the gap,
the bottom substrate facing the gap, in the gap. Where electrodes
are provided on both substrates, electrical contacts for coupling
the electrodes to a droplet actuator instrument for controlling or
monitoring the electrodes may be associated with one or both
plates. In some cases, electrodes on one substrate are electrically
coupled to the other substrate so that only one substrate is in
contact with the droplet actuator. In one embodiment, a conductive
material (e.g., an epoxy, such as MASTER BOND.TM. Polymer System
EP79, available from Master Bond, Inc., Hackensack, N.J.) provides
the electrical connection between electrodes on one substrate and
electrical paths on the other substrates, e.g., a ground electrode
on a top substrate may be coupled to an electrical path on a bottom
substrate by such a conductive material. Where multiple substrates
are used, a spacer may be provided between the substrates to
determine the height of the gap therebetween and define dispensing
reservoirs. The spacer height may, for example, be from about 5
.mu.m to about 600 .mu.m, or about 100 .mu.m to about 400 .mu.m, or
about 200 .mu.m to about 350 .mu.m, or about 250 .mu.m to about 300
.mu.m, or about 275 .mu.m. The spacer may, for example, be formed
of a layer of projections form the top or bottom substrates, and/or
a material inserted between the top and bottom substrates. One or
more openings may be provided in the one or more substrates for
forming a fluid path through which liquid may be delivered into the
droplet operations gap. The one or more openings may in some cases
be aligned for interaction with one or more electrodes, e.g.,
aligned such that liquid flowed through the opening will come into
sufficient proximity with one or more droplet operations electrodes
to permit a droplet operation to be effected by the droplet
operations electrodes using the liquid. The one or more openings
may in some cases serve as vents for releasing liquid or gas from
within the droplet operations gap. In some cases, the openings may
be sealed or covered with a permeable material such as a membrane.
For example a membrane having oleophobicity and hydrophobicity,
such as VERSAPOR.RTM. Membrane (Pall Corp., Port Washington, N.Y.)
may be used to cover an opening to facilitate escape of gasses
while preventing escape of oil and aqueous liquids. The base (or
bottom) and top substrates may in some cases be formed as one
integral component, such as a folded or layered plastic or layered
semiconductor construction. One or more reference electrodes may be
provided on the base (or bottom) and/or top substrates and/or in
the gap. Examples of reference electrode arrangements are provided
in the above referenced patents and patent applications. In various
embodiments, the manipulation of droplets by a droplet actuator may
be electrode mediated, e.g., electrowetting mediated or
dielectrophoresis mediated or Coulombic force mediated. Examples of
other techniques for controlling droplet operations that may be
used in the droplet actuators of the invention include using
devices that induce hydrodynamic fluidic pressure, such as those
that operate on the basis of mechanical principles (e.g. external
syringe pumps, pneumatic membrane pumps, vibrating membrane pumps,
vacuum devices, centrifugal forces, piezoelectric/ultrasonic pumps
and acoustic forces); electrical or magnetic principles (e.g.
electroosmotic flow, electrokinetic pumps, ferrofluidic plugs,
electrohydrodynamic pumps, attraction or repulsion using magnetic
forces and magnetohydrodynamic pumps); thermodynamic principles
(e.g. gas bubble generation/phase-change-induced volume expansion);
other kinds of surface-wetting principles (e.g. electrowetting, and
optoelectrowetting, as well as chemically, thermally, structurally
and radioactively induced surface-tension gradients); gravity;
surface tension (e.g., capillary action): electrostatic forces
(e.g., electroosmotic flow): centrifugal flow (substrate disposed
on a compact disc and rotated); magnetic forces (e.g., oscillating
ions causes flow); magnetohydrodynamic forces; and vacuum or
pressure differential. In certain embodiments, combinations of two
or more of the foregoing techniques may be employed to conduct a
droplet operation in a droplet actuator of the invention.
Similarly, one or more of the foregoing may be used to deliver
liquid into a droplet operations gap, e.g., from a reservoir in
another device or from an external reservoir of the droplet
actuator (e.g., a reservoir associated with a droplet actuator
substrate and a flow path from the reservoir into the droplet
operations gap). Droplet operations surfaces of certain droplet
actuators of the invention may be made from hydrophobic materials
or may be coated or treated to make them hydrophobic. For example,
in some cases some portion or all of the droplet operations
surfaces may be derivatized with low surface-energy materials or
chemistries, e.g., by deposition or using in situ synthesis using
compounds such as poly- or per-fluorinated compounds in solution or
polymerizable monomers. Examples include TEFLON.RTM. AF (available
from DuPont, Wilmington, Del.), members of the cytop family of
materials, coatings in the FLUOROPEL.RTM. family of hydrophobic and
superhydrophobic coatings (available from Cytonix Corporation,
Beltsville, Md.), silane coatings, fluorosilane coatings,
hydrophobic phosphonate derivatives (e.g., those sold by Aculon,
Inc), and NOVEC.TM. electronic coatings (available from 3M Company,
St. Paul, Minn.), and other fluorinated monomers for
plasma-enhanced chemical vapor deposition (PECVD). In some cases,
the droplet operations surface may include a hydrophobic coating
having a thickness ranging from about 10 nm to about 1,000 nm.
Moreover, in some embodiments, the top substrate of the droplet
actuator includes an electrically conducting organic polymer, which
is then coated with a hydrophobic coating or otherwise treated to
make the droplet operations surface hydrophobic. For example, the
electrically conducting organic polymer that is deposited onto a
plastic substrate may be poly(3,4-ethylenedioxythiophene)
poly(styrenesulfonate) (PEDOT:PSS). Other examples of electrically
conducting organic polymers and alternative conductive layers are
described in Pollack et al., International Patent Application No.
PCT/US2010/040705, entitled "Droplet Actuator Devices and Methods,"
the entire disclosure of which is incorporated herein by reference.
One or both substrates may be fabricated using a printed circuit
board (PCB), glass, indium tin oxide (ITO)-coated glass, and/or
semiconductor materials as the substrate. When the substrate is
ITO-coated glass, the ITO coating is preferably a thickness in the
range of about 20 to about 200 nm, preferably about 50 to about 150
nm, or about 75 to about 125 nm, or about 100 nm. In some cases,
the top and/or bottom substrate includes a PCB substrate that is
coated with a dielectric, such as a polyimide dielectric, which may
in some cases also be coated or otherwise treated to make the
droplet operations surface hydrophobic. When the substrate includes
a PCB, the following materials are examples of suitable materials:
MITSUI.TM. BN-300 (available from MITSUI Chemicals America, Inc.,
San Jose Calif.); ARLON.TM. 11N (available from Arlon, Inc, Santa
Ana, Calif.).; NELCO.RTM. N4000-6 and N5000-30/32 (available from
Park Electrochemical Corp., Melville, N.Y.); ISOLA.TM. FR406
(available from Isola Group, Chandler, Ariz.), especially IS620;
fluoropolymer family (suitable for fluorescence detection since it
has low background fluorescence); polyimide family; polyester,
polyethylene naphthalate; polycarbonate; polyetheretherketone;
liquid crystal polymer, cyclo-olefin copolymer (COC); cyclo-olefin
polymer (COP); aramid; THERMOUNT.RTM. nonwoven aramid reinforcement
(available from DuPont. Wilmington, Del.); NOMEX.RTM. brand fiber
(available from DuPont, Wilmington, Del.); and paper. Various
materials are also suitable for use as the dielectric component of
the substrate. Examples include: vapor deposited dielectric, such
as PARYLENE.RTM. (especially on glass) and PARYLENE.TM. N
(available from Parylene Coating Services, Inc., Katy, Tex.);
TEFLON.RTM. AF coatings; cytop; soldermasks, such as liquid
photoimageable soldermasks (e.g., on PCB) like TAIYO.TM. PSR4000
series, TAIYO.TM. PSR and AUS series (available from Taiyo America,
Inc. Carson City, Nev.) (good thermal characteristics for
applications involving thermal control), and PROBIMER.TM. 8165
(good thermal characteristics for applications involving thermal
control (available from Huntsman Advanced Materials Americas Inc.,
Los Angeles, Calif.); dry film soldermask, such as those in the
VACREL.RTM. dry film soldermask line (available from DuPont,
Wilmington, Del.); film dielectrics, such as polyimide film (e.g.,
KAPTON.RTM. polyimide film, available from DuPont, Wilmington,
Del.), polyethylene, and fluoropolymers (e.g., FEP),
polytetrafluoroethylene; polyester; polyethylene naphthalate;
cyclo-olefin copolymer (COC); cyclo-olefin polymer (COP); any other
PCB substrate material listed above; black matrix resin; and
polypropylene. Droplet transport voltage and frequency may be
selected for performance with reagents used in specific assay
protocols. Design parameters may be varied, e.g., number and
placement of on-actuator reservoirs, number of independent
electrode connections, size (volume) of different reservoirs,
placement of magnets/bead washing zones, electrode size,
inter-electrode pitch, and gap height (between top and bottom
substrates) may be varied for use with specific reagents,
protocols, droplet volumes, etc. In some cases, a substrate of the
invention may derivatized with low surface-energy materials or
chemistries, e.g., using deposition or in situ synthesis using
poly- or per-fluorinated compounds in solution or polymerizable
monomers. Examples include TEFLON.RTM. AF coatings and
FLUOROPEL.RTM. coatings for dip or spray coating, and other
fluorinated monomers for plasma-enhanced chemical vapor deposition
(PECVD). Additionally, in some cases, some portion or all of the
droplet operations surface may be coated with a substance for
reducing background noise, such as background fluorescence from a
PCR substrate. For example, the noise-reducing coating may include
a black matrix resin, such as the black matrix resins available
from Toray industries, Inc., Japan. Electrodes of a droplet
actuator are typically controlled by a controller or a processor,
which is itself provided as part of a system, which may include
processing functions as well as data and software storage and input
and output capabilities. Reagents may be provided on the droplet
actuator in the droplet operations gap or in a reservoir fluidly
coupled to the droplet operations gap. The reagents may be in
liquid form, e.g., droplets, or they may be provided in a
reconstitutable form in the droplet operations gap or in a
reservoir fluidly coupled to the droplet operations gap.
Reconstitutable reagents may typically be combined with liquids for
reconstitution. An example of reconstitutable reagents suitable for
use with the invention includes those described in Meathrel, et
al., U.S. Pat. No. 7,727,466, entitled "Disintegratable films for
diagnostic devices," granted on Jun. 1, 2010.
"Droplet operation" means any manipulation of a droplet on a
droplet actuator. A droplet operation may, for example, include:
loading a droplet into the droplet actuator, dispensing one or more
droplets from a source droplet; splitting, separating or dividing a
droplet into two or more droplets; transporting a droplet from one
location to another in any direction; merging or combining two or
more droplets into a single droplet; diluting a droplet; mixing a
droplet; agitating a droplet; deforming a droplet; retaining a
droplet in position; incubating a droplet; heating a droplet;
vaporizing a droplet; cooling a droplet; disposing of a droplet;
transporting a droplet out of a droplet actuator; other droplet
operations described herein; and/or any combination of the
foregoing. The terms "merge," "merging," "combine," "combining" and
the like are used to describe the creation of one droplet from two
or more droplets. It should be understood that when such a term is
used in reference to two or more droplets, any combination of
droplet operations that are sufficient to result in the combination
of the two or more droplets into one droplet may be used. For
example, "merging droplet A with droplet B," can be achieved by
transporting droplet A into contact with a stationary droplet B,
transporting droplet B into contact with a stationary droplet A, or
transporting droplets A and B into contact with each other. The
terms "splitting," "separating" and "dividing" are not intended to
imply any particular outcome with respect to volume of the
resulting droplets (i.e., the volume of the resulting droplets can
be the same or different) or number of resulting droplets (the
number of resulting droplets may be 2, 3, 4, 5 or more). The term
"mixing" refers to droplet operations which result in more
homogenous distribution of one or more components within a droplet.
Examples of "loading" droplet operations include microdialysis
loading, pressure assisted loading, robotic loading, passive
loading, and pipette loading. Droplet operations may be
electrode-mediated. In some cases, droplet operations are further
facilitated by the use of hydrophilic and/or hydrophobic regions on
surfaces and/or by physical obstacles. For examples of droplet
operations, see the patents and patent applications cited above
under the definition of "droplet actuator." Impedance or
capacitance sensing or imaging techniques may sometimes be used to
determine or confirm the outcome of a droplet operation. Examples
of such techniques are described in Sturmer et al., International
Patent Pub. No. WO/2008/101194, entitled "Capacitance Detection in
a Droplet Actuator," published on Aug. 21, 2008, the entire
disclosure of which is incorporated herein by reference. Generally
speaking, the sensing or imaging techniques may be used to confirm
the presence or absence of a droplet at a specific electrode. For
example, the presence of a dispensed droplet at the destination
electrode following a droplet dispensing operation confirms that
the droplet dispensing operation was effective. Similarly, the
presence of a droplet at a detection spot at an appropriate step in
an assay protocol may confirm that a previous set of droplet
operations has successfully produced a droplet for detection.
Droplet transport time can be quite fast. For example, in various
embodiments, transport of a droplet from one electrode to the next
may exceed about 1 sec, or about 0.1 sec, or about 0.01 sec, or
about 0.001 sec. In one embodiment, the electrode is operated in AC
mode but is switched to DC mode for imaging. It is helpful for
conducting droplet operations for the footprint area of droplet to
be similar to electrowetting area; in other words, 1.times.-,
2.times.-3.times.-droplets are usefully controlled operated using
1, 2, and 3 electrodes, respectively. If the droplet footprint is
greater than the number of electrodes available for conducting a
droplet operation at a given time, the difference between the
droplet size and the number of electrodes should typically not be
greater than 1; in other words, a 2.times. droplet is usefully
controlled using 1 electrode and a 3.times. droplet is usefully
controlled using 2 electrodes. When droplets include beads, it is
useful for droplet size to be equal to the number of electrodes
controlling the droplet, e.g., transporting the droplet.
"Filler fluid" means a fluid associated with a droplet operations
substrate of a droplet actuator, which fluid is sufficiently
immiscible with a droplet phase to render the droplet phase subject
to electrode-mediated droplet operations. For example, the droplet
operations gap of a droplet actuator is typically filled with a
filler fluid. The filler fluid may, for example, be a low-viscosity
oil, such as silicone oil or hexadecane filler fluid. The filler
fluid may fill the entire gap of the droplet actuator or may coat
one or more surfaces of the droplet actuator. Filler fluids may be
conductive or non-conductive. Filler fluids may, for example, be
doped with surfactants or other additives. For example, additives
may be selected to improve droplet operations and/or reduce loss of
reagent or target substances from droplets, formation of
microdroplets, cross contamination between droplets, contamination
of droplet actuator surfaces, degradation of droplet actuator
materials, etc. Composition of the filler fluid, including
surfactant doping, may be selected for performance with reagents
used in the specific assay protocols and effective interaction or
non-interaction with droplet actuator materials. Examples of filler
fluids and filler fluid formulations suitable for use with the
invention are provided in Srinivasan et al, International Patent
Pub. Nos. WO/2010/027894, entitled "Droplet Actuators, Modified
Fluids and Methods," published on Mar. 11, 2010, and
WO/2009/021173, entitled "Use of Additives for Enhancing Droplet
Operations," published on Feb. 12, 2009; Sista et al.,
International Patent Pub. No. WO/2008/098236, entitled "Droplet
Actuator Devices and Methods Employing Magnetic Beads," published
on Aug. 14, 2008; and Monroe et al., U.S. Patent Publication No.
20080283414, entitled "Electrowetting Devices," filed on May 17,
2007; the entire disclosures of which are incorporated herein by
reference, as well as the other patents and patent applications
cited herein.
"Immobilize" with respect to magnetically responsive beads, means
that the beads are substantially restrained in position in a
droplet or in filler fluid on a droplet actuator. For example, in
one embodiment, immobilized beads are sufficiently restrained in
position in a droplet to permit execution of a droplet splitting
operation, yielding one droplet with substantially all of the beads
and one droplet substantially lacking in the beads.
"Magnetically responsive" means responsive to a magnetic field.
"Magnetically responsive beads" include or are composed of
magnetically responsive materials. Examples of magnetically
responsive materials include paramagnetic materials, ferromagnetic
materials, ferrimagnetic materials, and metamagnetic materials.
Examples of suitable paramagnetic materials include iron, nickel,
and cobalt, as well as metal oxides, such as Fe3O4, BaFe12O19, CoO,
NiO, Mn2O3, Cr2O3, and CoMnP.
"Reservoir" means an enclosure or partial enclosure configured for
holding, storing, or supplying liquid. A droplet actuator system of
the invention may include on-cartridge reservoirs and/or
off-cartridge reservoirs. On-cartridge reservoirs may be (1)
on-actuator reservoirs, which are reservoirs in the droplet
operations gap or on the droplet operations surface; (2)
off-actuator reservoirs, which are reservoirs on the droplet
actuator cartridge, but outside the droplet operations gap, and not
in contact with the droplet operations surface: or (3) hybrid
reservoirs which have on-actuator regions and off-actuator regions.
An example of an off-actuator reservoir is a reservoir in the top
substrate. An off-actuator reservoir is typically in fluid
communication with an opening or flow path arranged for flowing
liquid from the off-actuator reservoir into the droplet operations
gap, such as into an on-actuator reservoir. An off-cartridge
reservoir may be a reservoir that is not part of the droplet
actuator cartridge at all, but which flows liquid to some portion
of the droplet actuator cartridge. For example, an off-cartridge
reservoir may be part of a system or docking station to which the
droplet actuator cartridge is coupled during operation. Similarly,
an off-cartridge reservoir may be a reagent storage container or
syringe which is used to force fluid into an on-cartridge reservoir
or into a droplet operations gap. A system using an off-cartridge
reservoir will typically include a fluid passage means whereby
liquid may be transferred from the off-cartridge reservoir into an
on-cartridge reservoir or into a droplet operations gap.
"Transporting into the magnetic field of a magnet," "transporting
towards a magnet," and the like, as used herein to refer to
droplets and/or magnetically responsive beads within droplets, is
intended to refer to transporting into a region of a magnetic field
capable of substantially attracting magnetically responsive beads
in the droplet. Similarly, "transporting away from a magnet or
magnetic field," "transporting out of the magnetic field of a
magnet," and the like, as used herein to refer to droplets and/or
magnetically responsive beads within droplets, is intended to refer
to transporting away from a region of a magnetic field capable of
substantially attracting magnetically responsive beads in the
droplet, whether or not the droplet or magnetically responsive
beads is completely removed from the magnetic field. It will be
appreciated that in any of such cases described herein, the droplet
may be transported towards or away from the desired region of the
magnetic field, and/or the desired region of the magnetic field may
be moved towards or away from the droplet. Reference to an
electrode, a droplet, or magnetically responsive beads being
"within" or "in" a magnetic field, or the like, is intended to
describe a situation in which the electrode is situated in a manner
which permits the electrode to transport a droplet into and/or away
from a desired region of a magnetic field, or the droplet or
magnetically responsive beads is/are situated in a desired region
of the magnetic field, in each case where the magnetic field in the
desired region is capable of substantially attracting any
magnetically responsive beads in the droplet. Similarly, reference
to an electrode, a droplet, or magnetically responsive beads being
"outside of" or "away from" a magnetic field, and the like, is
intended to describe a situation in which the electrode is situated
in a manner which permits the electrode to transport a droplet away
from a certain region of a magnetic field, or the droplet or
magnetically responsive beads is/are situated away from a certain
region of the magnetic field, in each case where the magnetic field
in such region is not capable of substantially attracting any
magnetically responsive beads in the droplet or in which any
remaining attraction does not eliminate the effectiveness of
droplet operations conducted in the region. In various aspects of
the invention, a system, a droplet actuator, or another component
of a system may include a magnet, such as one or more permanent
magnets (e.g., a single cylindrical or bar magnet or an array of
such magnets, such as a Halbach array) or an electromagnet or array
of electromagnets, to form a magnetic field for interacting with
magnetically responsive beads or other components on chip. Such
interactions may, for example, include substantially immobilizing
or restraining movement or flow of magnetically responsive beads
during storage or in a droplet during a droplet operation or
pulling magnetically responsive beads out of a droplet.
"Washing" with respect to washing a bead means reducing the amount
and/or concentration of one or more substances in contact with the
bead or exposed to the bead from a droplet in contact with the
bead. The reduction in the amount and/or concentration of the
substance may be partial, substantially complete, or even complete.
The substance may be any of a wide variety of substances: examples
include target substances for further analysis, and unwanted
substances, such as components of a sample, contaminants, and/or
excess reagent. In some embodiments, a washing operation begins
with a starting droplet in contact with a magnetically responsive
bead, where the droplet includes an initial amount and initial
concentration of a substance. The washing operation may proceed
using a variety of droplet operations. The washing operation may
yield a droplet including the magnetically responsive bead, where
the droplet has a total amount and/or concentration of the
substance which is less than the initial amount and/or
concentration of the substance. Examples of suitable washing
techniques are described in Pamula et al., U.S. Pat. No. 7,439,014,
entitled "Droplet-Based Surface Modification and Washing," granted
on Oct. 21, 2008, the entire disclosure of which is incorporated
herein by reference.
The terms "top," "bottom," "over," "under," and "on" are used
throughout the description with reference to the relative positions
of components of the droplet actuator, such as relative positions
of top and bottom substrates of the droplet actuator. It will be
appreciated that the droplet actuator is functional regardless of
its orientation in space.
When a liquid in any form (e.g., a droplet or a continuous body,
whether moving or stationary) is described as being "on", "at", or
"over" an electrode, array, matrix or surface, such liquid could be
either in direct contact with the electrode/array/matrix/surface,
or could be in contact with one or more layers or films that are
interposed between the liquid and the
electrode/array/matrix/surface.
When a droplet is described as being "on" or "loaded on" a droplet
actuator, it should be understood that the droplet is arranged on
the droplet actuator in a manner which facilitates using the
droplet actuator to conduct one or more droplet operations on the
droplet, the droplet is arranged on the droplet actuator in a
manner which facilitates sensing of a property of or a signal from
the droplet, and/or the droplet has been subjected to a droplet
operation on the droplet actuator.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates an exploded view of an example of a droplet
actuator that is suitable for using impedance detection as a
mechanism of microfluidics feedback in a droplet actuator;
FIG. 2 illustrates a top down view of the droplet actuator of FIG.
1 when its components are fully assembled;
FIG. 3 illustrates a top view of an electrode arrangement of the
droplet actuator of FIG. 1;
FIGS. 4A and 4B illustrate top views of a portion of the electrode
arrangement of the droplet actuator of FIG. 1 and show more details
of certain reservoir electrodes;
FIGS. 5A through 5H illustrate top views of the electrode
arrangement of the droplet actuator of FIG. 1 and examples of the
electrode activation during certain impedance detection
operations;
FIGS. 6 through 16 illustrate graphs of examples of impedance
measurements taken of certain electrodes of the droplet actuator of
FIG. 1 and under various conditions;
FIG. 17 illustrates a schematic diagram of an example of an
impedance sensing circuit of a droplet actuator that includes an
electrowetting voltage suppression mechanism for reducing
noise;
FIG. 18 illustrates a schematic diagram showing more details of the
impedance sensing circuit of FIG. 17 that includes the
electrowetting voltage suppression mechanism;
FIG. 19 illustrates a schematic diagram of the detection circuit of
an impedance sensing system that includes a feature for logging a
saturation condition of the response signal;
FIG. 20 illustrates an example of an excitation plot in relation to
a response plot of an impedance sensing system showing a response
non-saturation condition and a response saturation condition;
FIG. 21 illustrates a top down view of the droplet actuator of FIG.
1 that further includes an oil sensing electrode:
FIG. 22 illustrates a top view of a portion of a droplet actuator
in which the input port of an on-actuator reservoir is not directly
over any portion of the reservoir electrode;
FIGS. 23A and 23B illustrate top views of two electrode
arrangements, respectively, which are examples of electrode
configurations for helping to detect whether a sample reservoir is
fully loaded;
FIGS. 24A, 24B, and 24C illustrate top views of three electrode
arrangements, respectively, which are more examples of electrode
configurations for helping to detect whether a sample reservoir is
fully loaded.
6 DESCRIPTION
The present invention is microfluidic feedback methods using
impedance detection with respect to electrodes of droplet
actuators. For example, the microfluidic feedback methods of the
invention may correlate impedance measurements to the presence or
absence of liquid at certain electrodes of a droplet actuator, such
as at certain droplet operations electrodes and/or certain
reservoir electrodes. In this way, impedance detection operations
may be used to verify and/or monitor the presence or absence of
liquid at a certain electrode in a droplet actuator. Additionally,
certain actions may be taken in the protocol that is executing on
the droplet actuator based on the presence or absence of liquid at
a certain electrode, as determined using impedance detection
according to the present invention.
Certain embodiments of the invention include improved impedance
sensing circuits. In one example, the impedance sensing circuit
provides a mechanism for reducing, preferably entirely eliminating,
noise on the reference voltage power supply during impedance
detection operations. In another example, the impedance sensing
circuit provides a mechanism for flagging a saturation condition
with respect to the response signal.
6.1 Digital Microfluidics
Digital microfluidic technology conducts droplet operations on
discrete droplets by electrical control of their surface tension
(electrowetting). The droplets may be sandwiched between two
substrates, a bottom substrate and a top substrate separated by a
gap. The bottom substrate may, for example, be a printed circuit
board (PCB) with an arrangement of electrically addressable
electrodes. The top substrate may, for example, be an injection
molded plastic top substrate with a reference electrode plane made,
for example, from conductive ink or indium-tin oxide (ITO). The
bottom substrate and the top substrate may be coated with a
hydrophobic material. The space around the droplets (i.e., the gap
between bottom and top substrates) may be filled with an immiscible
inert fluid, such as silicone oil, to prevent evaporation of the
droplets and to facilitate their transport within the device. An
electric field, formed when voltage is applied to a control
electrode on the bottom substrate, reduces the interfacial tension
between the droplet and the electrode. This effect may be used to
transport droplets using surface energy gradients established by
activating a pattern of control electrodes on the bottom substrate
along any path of contiguous electrodes. Other droplet operations
may be effected by varying the patterns of voltage activation;
examples include merging, splitting, mixing, and dispensing of
droplets.
6.2 Methods of Microfluidic Feedback Using Impedance Detection
FIG. 1 illustrates an exploded view of an example of a droplet
actuator 100 that may be used to provide microfluidic feedback
using impedance detection. In one embodiment, droplet actuator 100
is configured for integrated sample preparation and nucleic acid
testing of a single sample. Droplet actuator 100 may include a
bottom substrate 110 and a top substrate 112. A gasket 114 may be
sandwiched between bottom substrate 110 and top substrate 112.
In one example, bottom substrate 110 may be a PCB that has an
electrode arrangement 116 and a set of power/signal input/output
(I/O) pads 118 patterned thereon. Electrode arrangement 116 may
include, for example, reservoir electrodes 120a through 120f that
are associated with reservoirs R1 through R6, respectively.
Electrode arrangement 116 may also include a sample reservoir
electrode 122 that is associated with a sample reservoir R7.
Reservoir electrodes 120a through 120f and sample reservoir
electrode 122 are arranged in relation to a path, line, and/or
array of droplet operations electrodes 124 (e.g., electrowetting
electrodes). Sample reservoir electrode 122 may be segmented into
an arrangement of multiple individually controlled electrodes,
which is shown with reference to FIGS. 2 and 3. Droplet operations
are conducted atop these various electrodes on a droplet operations
surface. More details of electrode arrangement 116 are described
with reference to FIGS. 2, 3, 4A, and 4B.
Top substrate 112 may be formed of a material that is substantially
transparent to visible light, ultraviolet (UV) light, and/or any
wavelength light of interest. For example, top substrate 112 may be
formed of glass, injection-molded plastic, and/or silicon.
Additionally, top substrate 112 may be coated with ITO, thereby
providing an electrical ground plane.
A clearance region is provided in gasket 114. When bottom substrate
110, top substrate 112, and gasket 114 are assembled together, the
clearance region of gasket 114 forms a gap between bottom substrate
110 and top substrate 112 at the droplet operations surface. The
thickness of gasket 114 may be used to set the height of the gap.
Further, the shape of the clearance region of gasket 114
substantially corresponds to the shape of electrode arrangement 116
of bottom substrate 110. In one example, the shape of the clearance
region of gasket 114 at reservoir electrodes 120a through 120f and
at sample reservoir electrode 122, together with bottom substrate
110 and top substrate 112, form reservoirs R1 through R6 and sample
reservoir R7. Reservoirs R1 through R6 and sample reservoir R7 are
examples of on-actuator reservoirs. Reservoirs R1 through R6 may
be, for example, reagent reservoirs for holding/dispensing various
reagent fluids, such as, but not limited to, elution buffer
solution and wash buffer solution. Respective input ports 134
(e.g., input ports 134a through 134f) of reservoirs R1 through R6
may be integrated into top substrate 112.
Sample reservoir R7 may be provided for preparing and dispensing
sample fluids. Sample reservoir R7 may be of sufficient size to
contain a large volume of fluid, e.g., about 1.5 mL. One or more
input ports of sample reservoir R7 may be integrated into top
substrate 112. For example, an input port 128 for loading sample
fluids into sample reservoir R7 may be integrated into top
substrate 112. Additionally, an input port 130 for loading sample
preparation reagents (e.g., lysis buffer, nucleic acid capture
beads) into sample reservoir R7 may be integrated into top
substrate 112. Top substrate 112 may include certain features (not
shown) for helping define the volume of the on-actuator reservoirs
(e.g., reservoirs R1 through R6 and sample reservoir R7).
When bottom substrate 110, top substrate 112, and gasket 114 are
assembled together, input port 128 and input port 130 in top
substrate 112 are substantially aligned with at least a portion of
sample reservoir electrode 122 of bottom substrate 110. Similarly,
input ports 134 in top substrate 112 are substantially aligned with
at least a portion of their respective reservoir electrodes 120 of
bottom substrate 110. More details of droplet actuator 100 are
described with reference to FIGS. 2 through 5H.
A port (e.g., input port 128, input port 130, and input ports 134)
is an entrance/exit (opening) to the droplet operations gap. Liquid
may flow through the port into any portion of the gap. That could
be into a reservoir region of the gap or onto a droplet operations
pathway. A port may be used to fill the gap with filler fluid.
However, in most cases, a reagent fluid or sample fluid flowing
through a port should come into sufficient proximity with an
electrode, such that the electrode can be used to conduct one or
more droplet operations using the liquid, such as droplet
transport, splitting, and dispensing.
Additionally, the gap height at sample reservoir R7 may be greater
than the gap height at reservoirs R1 through R6 and/or along
unit-sized droplet operations electrodes 124. For example, the gap
height at sample reservoir R7 may be about >3 mm to facilitate
storage of larger liquid volumes (e.g., about 1.5 mL) and ready
dispensing of droplets. While the gap height at reservoirs R1
through R6 and/or along droplet operations electrodes 124 may be
about 250-500 .mu.m in order to facilitate, for example, rapid
transport, mixing, washing, and/or incubation of one or more
droplets. The gap height transition region may be at the dispensing
end of sample reservoir R7, which is the portion of sample
reservoir R7 that feeds the line of droplet operations electrodes
124.
An imaging system 150 may be used in combination with droplet
actuator 100. For example, a detection electrode 135 is provided at
the end of the line of droplet operations electrodes 124 that is
opposite sample reservoir R7. Accordingly, a detection window 136
may be included in top substrate 112 at detection electrode 135.
Imaging system 150 uses detection window 136 for performing
detection operations on any droplet atop detection electrode 135.
The amount of transparency provided at detection window 136 may
vary. Detection window 136 may be formed to direct and/or filter
light, e.g., formed as a lens and/or as an optical filter that
excludes certain wavelengths. Light energy that is generated in the
gap of droplet actuator 100 may be transmitted through detection
window 136 and then captured by imaging system 150. In one example,
imaging system 150 may include one or more light-emitting diodes
(LEDs) 152 (i.e., an illumination source) and a digital image
capture device, such as a charge-coupled device (CCD) camera 154.
(Only the lens of CCD camera 154 is shown in FIG. 1). In one
example, one LED 152 may emit green light (525 nm wavelength) and
another LED 152 may emit red light (635 nm wavelength).
FIG. 2 illustrates a top down view of droplet actuator 100 when its
components are fully assembled. More specifically, FIG. 2 shows
bottom substrate 110, top substrate 112, and gasket 114 assembled
together to form droplet actuator 100. FIG. 2 shows that the
clearance region of gasket 114 substantially corresponds to the
shape of electrode arrangement 116 of bottom substrate 110.
Additionally, the alignment is shown of sample reservoir R7 to
sample reservoir electrode 122 of bottom substrate 110. Similarly,
the alignment is shown of reservoirs R1 through R6 to their
respective reservoir electrodes 120 of bottom substrate 110.
I/O pads 118 are contacts that are connected by wiring traces to
the electrodes, such as to reservoir electrodes 120, sample
reservoir electrode 122, and droplet operations electrodes 124. In
one example, I/O pads 118 are used for applying electrowetting
voltages. When a droplet actuator, such as droplet actuator 100, is
installed in a microfluidics system (not shown), I/O pads 118 are
coupled to a controller, which includes the circuitry for detecting
impedance at a specific electrode. One I/O pad 118 may be coupled
to top substrate 112 to provide the return path for the circuit.
FIG. 2 also shows an impedance sensing system 170, which is one
example of circuitry for detecting impedance at a specific
electrode. Impedance sensing system 170 may be, for example, an
impedance spectrometer.
Impedance sensing system 170 may be used to monitor the capacitive
loading of any electrode with or without liquid thereon. For
examples of suitable capacitance detection techniques, see Sturmer
et al., International Patent Publication No. WO/2008/101194,
entitled "Capacitance Detection in a Droplet Actuator," published
on Aug. 21, 2008; and Kale et al., International Patent Publication
No. WO/2002/080822, entitled "System and Method for Dispensing
Liquids," published on Oct. 17, 2002; the entire disclosures of
which are incorporated herein by reference.
According to the invention, impedance sensing system 170 may be
used to capture an impedance measurement between any electrode of
bottom substrate 110 and the ground reference electrode of top
substrate 112. For example, impedance sensing system 170 may be
used to scan the reservoir electrodes 120, sample reservoir
electrode 122, and droplet operations electrodes 124. An impedance
measurement may be stored for each individual electrode of droplet
actuator 100. For example, the microfluidic feedback methods of the
invention may use impedance measurements taken by impedance sensing
system 170 to determine the presence or absence of liquid at
certain electrodes of droplet actuator 100, such as at certain
reservoir electrodes 120, sample reservoir electrode 122, and
certain droplet operations electrodes 124.
FIG. 3 illustrates a top view of electrode arrangement 116 of
droplet actuator 100 of FIG. 1. Again, electrode arrangement 116
includes reservoir electrodes 120a through 120f and sample
reservoir electrode 122, which are arranged in relation to the
droplet operations electrodes 124. When droplet actuator 100 is in
use, in one example, reservoir R1 at reservoir electrode 120a may
be filled with elution buffer solution, reservoir R3 at reservoir
electrode 120c may be filled with wash buffer solution, reservoir
R3 at reservoir electrode 120f may be also filled with wash buffer
solution, and sample reservoir R7 at sample reservoir electrode 122
may be filled with sample fluid.
FIGS. 4A and 4B illustrate top views of a portion of electrode
arrangement 116 of droplet actuator 100 of FIG. 1 and show more
details of reservoir electrodes 120a through 120f of reservoirs R1
through R6, respectively. Each of the reservoirs R1 through R6 may
have three electrodes in the path leading to the line of droplet
operations electrodes 124. For example, at the dispensing side of
each of the reservoirs R1 through R6 may be two dispensing
electrodes 160 followed by a gate electrode 162. Gate electrode 162
is nearest the droplet operations electrodes 124.
FIG. 4A shows a volume of fluid 164 atop, for example, reservoir
electrode 120a of reservoir R1. In this example, the fluid 164 is
positioned substantially within the boundaries of reservoir
electrode 120a. However, when there is some volume of fluid atop
any reservoir electrode, there is a risk of the fluid drifting
toward the line of droplet operations electrodes 124, as shown in
FIG. 4B. If the droplet operations electrode 124 near, for example,
gate electrode 162 of reservoir R1 happens to be activated, there
is a risk of some of this fluid merging with other droplets (not
shown) moving along the path of droplet operations electrodes 124.
Therefore, a microfluidics feedback mechanism, such as impedance
measurements taken of dispensing electrodes 160 and gate electrode
162 of reservoir R1, may be useful to monitor the position of fluid
164 in reservoir R1. If it is detected that that fluid 164 is
drifting toward droplet operations electrodes 124, fluid 164 can be
pulled back into the reservoir by, for example, activating
reservoir electrode 120a of reservoir R1. In this way, any chance
of fluid 164 in reservoir R1 interfering with other droplets moving
along droplet operations electrodes 124 may be reduced, preferably
entirely eliminated. An example of using impedance detection to
monitor and/or verify the presence or absence of fluid on, for
example, certain electrodes of droplet actuator 100 is described
with reference to FIGS. 5A through 17.
FIGS. 5A through 5H illustrate top views of electrode arrangement
116 of droplet actuator 100 of FIG. 1 and an example of an
electrode activation sequence of certain impedance detection
operations. The electrode activation sequence and impedance
detection operations of FIGS. 5A through 5H is one example of a
microfluidics feedback mechanism in a droplet actuator.
Referring to FIG. 5A, reservoir electrode 120a of reservoir R1 and
reservoir electrode 120b of reservoir R2 are activated and an
impedance measurement is taken of reservoir electrode 120a and
reservoir electrode 120b (together) using, for example, impedance
sensing system 170 of FIG. 2.
Referring to FIG. 5B, reservoir electrode 120c of reservoir R3 is
activated and an impedance measurement is taken of reservoir
electrode 120c using impedance sensing system 170 of FIG. 2.
Referring to FIG. 5C, gate electrode 162 of reservoir R3 is
activated and an impedance measurement is taken of this gate
electrode 162 using impedance sensing system 170 of FIG. 2.
Referring to FIG. 5D, reservoir electrode 120d of reservoir R4 is
activated and an impedance measurement is taken of reservoir
electrode 120d using impedance sensing system 170 of FIG. 2.
Referring to FIG. 5E, reservoir electrode 120e of reservoir R5 is
activated and an impedance measurement is taken of reservoir
electrode 120e using impedance sensing system 170 of FIG. 2.
Referring to FIG. 5F, reservoir electrode 120f of reservoir R6 is
activated and an impedance measurement is taken of reservoir
electrode 120f using impedance sensing system 170 of FIG. 2.
Referring to FIG. 5G, gate electrode 162 of reservoir R6 is
activated and an impedance measurement is taken of this gate
electrode 162 using impedance sensing system 170 of FIG. 2.
Referring to FIG. 5H, sample reservoir electrode 122 of sample
reservoir R7 is activated and an impedance measurement is taken of
sample reservoir electrode 122 using impedance sensing system 170
of FIG. 2.
With respect to FIGS. 5A through 5H, there is an expected
difference in the impedance measurement readings when filler oil
only is at the electrode vs. when fluid is present at the
electrode. Examples of the results of multiple impedance detection
operations of droplet actuator 100 are shown with reference to
FIGS. 6 through 16.
FIGS. 6 through 16 illustrate graphs of examples of impedance
measurements taken of certain electrodes of droplet actuator 100 of
FIG. 1 and under the various conditions and with the electrode
activation shown in FIGS. 5A through 5H. For example, a set of
impedance measurements were taken of certain electrodes of droplet
actuator 100 with filler oil only at the electrodes of interest.
Then, another set of impedance measurements were taken of certain
electrodes of droplet actuator 100 with fluid at the electrodes.
The graphs shown in FIGS. 6 through 16 are provided to show the
contrast between the impedance measurements taken under the two
different conditions, thereby demonstrating the use of impedance
detection operations as a suitable microfluidic feedback mechanism
for determining the presence or absence of fluid at any electrode
of interest.
Referring to FIG. 6, a bar graph 700 shows the impedance
measurements acquired with filler oil only in the gap of droplet
actuator 100. That is, the gap of droplet actuator 100 is loaded
with filler oil and this set of impedance measurements is acquired
prior to loading droplet actuator 100 with any other fluids.
Therefore, bar graph 700 shows pre-liquid loading impedance values
at certain reservoirs of droplet actuator 100. The set of impedance
readings shown in bar graph 700 may be referred to as the "blank
values." By way of example, multiple detection operations (or runs)
were performed and plotted in bar graph 700. For example, seven
detection operations (runs 1 through 7) were performed and recorded
with respect to reservoir R1 and reservoir R2 (see FIG. 5A),
reservoir R3 (see FIG. 5B), reservoir R4 (see FIG. 5D), reservoir
R5 (see FIG. 5E), reservoir R6 (see FIG. 5F), and sample reservoir
R7 (see FIG. 5H) of droplet actuator 100. Run 5 is not shown due to
technical problem during the run. Runs 1 through 7 may be the
results of detection operations performed on one or more instances
of droplet actuator 100. The impedance values in bar graph 700 and
in subsequent bar graphs and plots are given in ohms.
Bar graph 700 shows some variation in the blank values of sample
reservoir R7. During runs 1 through 7 an air bubble is
intentionally left in sample reservoir R7. A variation in the
position of this bubble from one run to the next may contribute to
the variation in the blank values. Additionally, the presence of
the two openings in top substrate 112 at sample reservoir R7 (i.e.,
input ports 128 and 130) may contribute to the variation in the
blank values of sample reservoir R7.
In contrast to the pre-liquid loading impedance values of bar graph
700, FIG. 7 shows a bar graph 800 that shows the impedance
measurements acquired with fluid present at certain reservoirs of
droplet actuator 100. That is, bar graph 800 shows post-liquid
loading impedance values at certain reservoirs of droplet actuator
100. For example, bar graph 800 shows a plot of another set of
seven detection operations (runs 1 through 7). In runs 1, 2, and 3,
reservoir R3, reservoir R6, and sample reservoir R7 are loaded with
a certain amount of fluid. In runs 4, 5, 6, and 7, reservoir R1,
reservoir R3, reservoir R6, and sample reservoir R7 are loaded with
a certain amount of fluid.
Reservoir R3, reservoir R6, and sample reservoir R7 are used in all
runs, while reservoir R1 is only used in runs 4 through 7. The
impedance values at reservoir R3 and reservoir R6, which are used
in all runs, are consistent across runs. The impedance value at
sample reservoir R7 is consistent across runs, unlike the blank
values of sample reservoir R7 shown in bar graph 700 of FIG. 6.
Referring to FIG. 8, a bar graph 900 shows a plot of the liquid
loading delta Z values. That is, bar graph 900 shows the difference
(called delta Z) between the pre-liquid loading impedance values of
bar graph 700 of FIG. 6 and the post-liquid loading impedance
values of bar graph 800 of FIG. 7. Bar graph 900 indicates
noticeable delta Z values between reservoirs that are loaded with
fluid and reservoirs that are not loaded, which shows clear
separation between loaded and empty reservoirs.
Referring to FIG. 9A, a plot 1000 of the pre-dispense impedance
values at reservoir R3 is shown with respect to 10 droplets. That
is, 10 droplets are dispensed from reservoir R3 of droplet actuator
100 and an impedance measurement is taken on reservoir electrode
120c of reservoir R3 just prior to the dispensing of each droplet.
By contrast and referring now to FIG. 9B, a plot 1050 of the
post-dispense impedance values at reservoir R3 is shown with
respect to the same 10 droplets. That is, when the 10 droplets are
dispensed from reservoir R3 of droplet actuator 100, an impedance
measurement is taken on reservoir electrode 120c of reservoir R3
just after the dispensing of each droplet. Again, seven runs of
pre-dispense impedance values and post-dispense impedance values
are collected. The seven runs may include one or more instances of
droplet actuator 100.
Referring to plot 1000 of FIG. 9A, there may be some variation in
the pre-dispense impedance values of the droplet #1 of runs 1
through 7, which may be due to variation in the position of the
fluid that is loaded in reservoir R3. This variation is not seen in
the post-dispense curves of plot 1050 of FIG. 9B.
Referring to FIG. 10, a plot 1100 of the pre-dispense impedance
values at gate electrode 162 of reservoir R3 is shown with respect
to 10 droplets. That is, 10 droplets are dispensed from reservoir
R3 of droplet actuator 100. As each droplet passes atop the gate
electrode 162 of reservoir R3 an impedance measurement is acquired.
FIG. 10 also shows a table that includes for each of the seven runs
(1) the average pre-dispense impedance value of the 10 droplets,
(2) the standard deviation, and (3) the percent capacitance-voltage
(CV %).
By contrast and referring now to FIG. 11, a plot 1200 of the
post-dispense impedance values at gate electrode 162 of reservoir
R3 is shown with respect to the same 10 droplets. That is, 10
droplets are dispensed from reservoir R3 of droplet actuator 100.
As each of the 10 droplets is transported off of the gate electrode
162 of reservoir R3 an impedance measurement is acquired. FIG. 11
also shows a table that includes for each of the seven runs (1) the
average post-dispense impedance value of the 10 droplets, (2) the
standard deviation, and (3) the CV %.
Referring to FIG. 12, a bar graph 1300 shows a plot of the delta Z
values of gate electrode 162 of reservoir R3. That is, bar graph
1300 shows the difference (called delta Z) between the pre-dispense
impedance values of bar graph 1100 of FIG. 10 and the post-dispense
impedance values of bar graph 1200 of FIG. 11. FIG. 12 also shows a
table that includes for each of the seven runs (1) the average
delta Z value, (2) the standard deviation of the delta Z values,
and (3) the CV % of the delta Z values. Additionally, the table
shows the average delta Z value of all runs, the standard deviation
of the delta Z value of all runs, and the CV % of the delta Z value
of all runs.
Referring to FIG. 13A, a plot 1400 of the pre-dispense impedance
values at reservoir R6 is shown with respect to 10 droplets. That
is, 10 droplets are dispensed from reservoir R6 of droplet actuator
100 and an impedance measurement is taken on reservoir electrode
120f of reservoir R6 just prior to the dispensing of each droplet.
By contrast and referring now to FIG. 13B, a plot 1450 of the
post-dispense impedance values at reservoir R6 is shown with
respect to the same 10 droplets. That is, when the 10 droplets are
dispensed from reservoir R6 of droplet actuator 100, an impedance
measurement is taken on reservoir electrode 120f of reservoir R6
just after the dispensing of each droplet. Again, seven runs of
pre-dispense impedance values and post-dispense impedance values
are collected. The seven runs may include one or more instances of
droplet actuator 100.
Referring to plot 1400 of FIG. 13A, there may be some variation in
the pre-dispense impedance values of the droplet #1 of runs 1
through 7, which may be due to variation in the position of the
fluid that is loaded in reservoir R6. This variation is not seen in
the post-dispense curves of plot 1450 of FIG. 13B.
Referring to FIG. 14, a plot 1500 of the pre-dispense impedance
values at gate electrode 162 of reservoir R6 is shown with respect
to 10 droplets. That is, 10 droplets are dispensed from reservoir
R6 of droplet actuator 100. As each droplet passes atop the gate
electrode 162 of reservoir R6 an impedance measurement is acquired.
FIG. 14 also shows a table that includes for each of the seven runs
(1) the average pre-dispense impedance value of the 10 droplets,
(2) the standard deviation, and (3) the CV %.
By contrast and referring now to FIG. 15, a plot 1600 of the
post-dispense impedance values at gate electrode 162 of reservoir
R6 is shown with respect to the same 10 droplets. That is, 10
droplets are dispensed from reservoir R6 of droplet actuator 100.
As each of the 10 droplets is transported off of the gate electrode
162 of reservoir R6 an impedance measurement is acquired. FIG. 15
also shows a table that includes for each of the seven runs (1) the
average post-dispense impedance value of the 10 droplets, (2) the
standard deviation, and (3) the CV %.
Referring to FIG. 16, a bar graph 1700 shows a plot of the delta Z
values of gate electrode 162 of reservoir R6. That is, bar graph
1700 shows the difference (called delta Z) between the pre-dispense
impedance values of plot 1500 of FIG. 14 and the post-dispense
impedance values of plot 1600 of FIG. 15. FIG. 16 also shows a
table that includes for each of the seven runs (1) the average
delta Z value, (2) the standard deviation of the delta Z values,
and (3) the CV % of the delta Z values. Additionally, the table
shows the average delta Z value of all runs, the standard deviation
of the delta Z value of all runs, and the CV % of the delta Z value
of all runs. Referring again to FIGS. 1 through 16, other variables
may effect impedance measurements. For example, temperature and/or
droplet size may have an effect on the impedance measurements.
6.2.1 Impedance Sensing Circuits
Currently, the impedance sensing circuit that is used with a
droplet actuator may utilize an impedance signal that is
superimposed on a reference voltage. The reference voltage source
is typically a switching power supply, which is a high voltage AC
power supply for providing the electrowetting voltage (e.g., about
300 volts) to the electrodes of a droplet actuator. The stability
of the high voltage AC power supply is critical because it is used
as the impedance reference measurement voltage. However, a drawback
of this arrangement is that switching power supplies may be noisy.
For example, in a droplet actuator application, a ripple voltage of
about 1 to about 3 volts may be present on the about 300V output.
While this ripple voltage is of little or no consequence when
performing droplet operations, it may contribute to certain
inaccuracies during impedance detection operations. Voltage
regulators, such as linear regulators, may be used to smooth out
the ripple. However, voltage regulators are not completely
effective in eliminating the noise, consume a large amount of power
at high voltages (e.g., about 300 volts), and add expense and
complexity to the circuit. Therefore, the impedance sensing circuit
of the present invention provides a novel approach that does not
rely on a voltage regulator to ensure stability of the high voltage
AC power supply during impedance detection operations. For example,
the impedance sensing circuit includes an electrowetting voltage
suppression mechanism for reducing noise during impedance detection
operations, which is described with reference to FIGS. 17 and
18.
FIG. 17 illustrates a schematic diagram of an example of an
impedance sensing circuit 1800 of a droplet actuator that includes
an electrowetting voltage suppression mechanism for reducing noise.
Impedance sensing circuit 1800 may include a power supply (PS)
1810. PS 1810 provides the electrowetting voltage source that is
needed to perform droplet operations. In one example, PS 1810 is a
300 VAC power supply. Impedance sensing circuit 1800 may also
include an impedance sensing system 1812. Impedance sensing system
1812 includes an excitation portion for generating an excitation
signal and a detection portion for processing the return
signal.
The excitation signal of impedance sensing system 1812 is
superimposed on the output of PS 1810 via, for example, a voltage
adder 1814. The output of voltage adder 1814 may be selectively
connected to any electrode of a droplet actuator. By way of
example, FIG. 17 shows the output of voltage adder 1814 selectively
connected to any reservoir electrode 120, sample reservoir
electrode 122, and/or any droplet operations electrode 124 of
droplet actuator 100 of FIGS. 1, 2, and 3. During impedance
detection operations, the return path (with respect to the
electrodes) to the detection portion of impedance sensing system
1812 is the electrical ground plane of the top substrate, such as
top substrate 112 of droplet actuator 100.
An aspect of the impedance sensing circuit 1800 of the invention is
that it also includes a mechanism for suppressing the output of PS
1810 during impedance detection operations, thereby reducing,
preferably entirely eliminating, noise on the output of PS 1810. In
this way, the accuracy and/or reliability of impedance measurements
taken by impedance sensing system 1812 may be improved. For
example, the switching action of PS 1810, which is the source of
the noise, is suppressed (i.e., stopped) during impedance detection
operations. Impedance sensing circuit 1800 includes a SUPPRESS
signal that feeds the control of PS 1810 for disabling the
switching action thereof during impedance detection operations.
More details of the suppression mechanism of the invention are
described with reference to FIG. 18.
FIG. 18 illustrates a schematic diagram showing more details of
impedance sensing circuit 1800 of FIG. 17 that includes the
electrowetting voltage suppression mechanism. In particular, FIG.
18 shows more details of an example of the voltage suppression
mechanism with respect to PS 1810. For example, PS 1810 includes a
direct current (DC) power source 1820, a transformer T1, and a
switching circuit 1822. DC power source 1820 and switching circuit
1822 are arranged in relation to the primary of transformer T1.
Switching circuit 1822 may include any solid state switch device,
such as an NMOS switch. In one example, the solid state switch
device may be toggled off and on by a square wave from an
oscillator (not shown). Switching circuit 1822 is used to develop a
low voltage AC signal at the primary of transformer T1. A standard
rectifier circuit at the secondary of transformer T1 provides an
output voltage (VAC) that is a higher voltage than the input
voltage. PS 1810 also includes a tank capacitor C1 at VAC (i.e., at
the secondary of transformer T1). A feedback loop is provided from
VAC back to switching circuit 1822.
In operation, the SUPPRESS signal feeds switching circuit 1822 of
PS 1810. For example, when the SUPPRESS signal is active the
switching action of the solid state switch device of PS 1810 is
stopped. In one example, during impedance detection operations, the
SUPPRESS signal is used to stop the switching action of PS 1810 for
several milliseconds while the impedance measurements are taking
place. Stopping the switching action reduces, preferably entirely
eliminates, any noise (i.e., voltage ripple) on the output of PS
1810. At the same time, tank capacitor C1 stores the charge at the
output of PS 1810. In this way, the output voltage of PS 1810 is
maintained while the switching action of PS 1810 is being
suppressed via the SUPPRESS signal. Once impedance measurements are
complete, the SUPPRESS signal may be deactivated and the normal
operation of PS 1810 resumes.
An example of a method of using impedance sensing circuit 1800 of
the invention may include, but is not limited to, the following
steps--(1) activate the SUPPRESS signal and, thereby, stop the
switching action of PS 1810; (2) activate the excitation portion of
impedance sensing system 1812 and, thereby, generate an excitation
signal to any one or more electrodes of interest; (3) process the
return signal(s) using the detection portion of impedance sensing
system 1812; (4) correlate the impedance measurements to the
presence and/or absence of fluid at the one or more electrodes of
interest; (5) deactivate the excitation portion of impedance
sensing system 1812; and (6) deactivate the SUPPRESS signal and,
thereby, resume normal operation of PS 1810.
FIG. 19 illustrates a schematic diagram of a detection circuit 2000
of an impedance sensing system that includes a feature for logging
a saturation condition of the response signal. In one example,
detection circuit 2000 may be the detection portion of impedance
sensing system 1812 of FIG. 17. Detection circuit 2000 may include,
for example, a current-to-voltage (I/V) converter 2010 and an
analog-to-digital (A/D) converter 2012. During an impedance
measurement, an excitation signal is generated and I/V converter
2010 receives the response signal that is returned through the
ground plane of the droplet actuator. I/V converter 2010 (e.g., an
operational amplifier (op amp) arrangement) converts the current of
the response signal to a voltage level, which feeds A/D converter
2012. A/D converter 2012 converts the voltage level to digital data
and, in particular, to MAGNITUDE and PHASE data to be processed. By
way of example, FIG. 20 illustrates an example of an excitation
plot 2100 in relation to a response plot 2105 of an impedance
sensing system. Further, response plot 2105 of FIG. 20 shows both a
response non-saturation condition and a response saturation
condition.
Excitation plot 2100 of FIG. 20 shows a plot of the excitation
signal voltage vs. time. For example, excitation plot 2100 shows a
plot of an excitation signal 2110, which is, for example, a sign
wave that has a certain frequency and amplitude. Response plot 2105
of FIG. 20 shows a plot of the response signal current vs. time.
For example, response plot 2105 shows a plot of a response signal
2120, which is, for example, a sign wave that has a certain
frequency and amplitude. Response signal 2120 is an example of a
signal at the input of I/V converter 2010. One output of A/D
converter 2012 is the relative phase (.DELTA.O), which is the
difference in phase between, for example, excitation signal 2110 of
excitation plot 2100 and response signal 2120 of response plot
2105. Referring to FIG. 19, this may be called PHASE data. Another
output of A/D converter 2012 is peak-to-peak amplitude of, for
example, response signal 2120 of response plot 2105. Referring to
FIG. 19, this may be called MAGNITUDE data.
There may be certain scenarios in which the response signal
response is saturated. That is, impedance sensing system is trying
to measure an admittance that is so high and an impedance that is
so low that the response signal is hitting the rails of what the
current sense amplifier (e.g., I/V converter 2010) can handle. For
example, response signal 2120 of response plot 2105 is an example
of a response signal that is in a non-saturation condition. By
contrast, response plot 2105 also shows a plot of a response signal
2122, which is an example of a response signal that is in a
saturation condition with respect to I/V converter 2010. For
example, a V-MAX and a V-MIN voltage is associated with I/V
converter 2010. Any response signal, such as response signal 2122,
reaching and/or exceeding the V-MAX and/or V-MIN thresholds is in
saturation (e.g., response signal 2122 shown flattened out at V-MAX
and V-MIN).
This saturation condition is not always evident in the mathematical
output of A/D converter 2012, which is MAGNITUDE and PHASE data.
That is, the digital MAGNITUDE and PHASE data of A/D converter 2012
is not always reliable to indicate a saturation condition.
Therefore, according to the invention, detection circuit 2000
includes a feature for logging a saturation condition of the
response signal during any impedance detection operation.
For example, in addition to feeding the input of A/D converter
2012, the output of I/V converter 2010 feeds a pair of comparators.
For example, the output of I/V converter 2010 is connected to the
positive input of a comparator 2014 and to the negative input of a
comparator 2016. A voltage V1 is provided at the negative input of
comparator 2014. A voltage V2 is provided at the positive input of
comparator 2016. V1 may be set just slightly above V-MIN and V2 may
be set just slightly below V-MAX (see response plot 2105 of FIG.
20).
The outputs of comparator 2014 and comparator 2016 feed an OR gate
2018. The output of OR gate 2018 feeds a latch 2020. The output of
latch 2020 provides a saturation FLAG signal. If the response
signal (e.g., response signal 2122 of response plot 2105 of FIG.
20) exceeds V1 or V2, the output of at least one of comparator 2014
and comparator 2016 transitions to a logic high. This causes the
output of OR gate 2018 to also go high and sets latch 2020, which
means the FLAG signal is active indicating that a saturation
condition is present. At beginning of any impedance detection
operation latch 2020 may be reset. However, at the end of any
impedance detection operation, the state of the FLAG signal is read
to determine whether a saturation condition occurred. In this way,
the impedance detection operation does not depend on the digital
MAGNITUDE and PHASE data alone to determine whether a saturation
condition has occurred.
6.2.2 Other Impedance Detection Mechanisms
FIG. 21 illustrates a top down view of droplet actuator 100 of FIG.
1 that further includes an oil sensing electrode. An impedance
detection operation of the oil sensing electrode may be used to
verify that the gap of the droplet actuator is fully filled with
filler oil. For example, patterned on the end of bottom substrate
110 that is nearest detection electrode 135 is an oil sensing
electrode 2210. A fluid path 2212 that leads to oil sensing
electrode 2210 is provided in gasket 114. In this way a small
on-actuator fluid reservoir is created at oil sensing electrode
2210.
In operation, filler oil may be injected into the end of droplet
actuator 100 that is opposite oil sensing electrode 2210.
Therefore, oil sensing electrode 2210 is the last location to fill
with oil. At the same time, using impedance detection, oil sensing
electrode 2210 may be monitored for the presence of oil thereon.
For example, filler oil may be injected into the gap of droplet
actuator 100 using input port 128 and/or input port 130 of sample
reservoir R7. The filler oil then flows in the direction from
sample reservoir R7 to oil sensing electrode 2210 in order to fill
the active area of droplet actuator 100. During the oil filling
process, oil sensing electrode 2210 is monitored using, for
example, impedance sensing system 170. As long the impedance
measurements of impedance sensing system 170 indicate that no oil
is present atop oil sensing electrode 2210, the filling process
continues. However, because the small fluid reservoir at oil
sensing electrode 2210 is the last location to fill with oil, as
soon as the impedance measurements of impedance sensing system 170
indicate that oil is present atop oil sensing electrode 2210, the
filling process is ended. The inclusion of an oil sensing
electrode, such as oil sensing electrode 2210, provides a way to
use impedance detection to ensure that the active area of droplet
actuator 100 is fully filled with oil, according to the present
invention.
FIG. 22 illustrates a top view of a portion of a droplet actuator
2300 in which the input port of an on-actuator reservoir is not
directly over any portion of the reservoir electrode. This
invention is an example of an arrangement for ensuring that a
reservoir is fully loaded. In this example, droplet actuator 2300
includes a reservoir electrode 2310 that has a loading port 2312 in
the top substrate (not shown) that is not directly over any portion
of reservoir electrode 2310. A reservoir boundary 2314 is shown
that defines the size, shape, and/or volume of the on-actuator
reservoir. The reservoir boundary 2314 may be established by, for
example, a gasket, features in the top substrate, features in the
bottom substrate, and/or any combinations thereof. A fluid path
2316 is present from loading port 2312 to reservoir electrode
2310.
Currently, when an input port (i.e., loading opening) of an
on-actuator reservoir is directly over the electrode, certain
variability of the fluid volume at the reservoir may occur. This
variability may be indicated by impedance measurement variability
of the reservoir electrode during filling and/or use. Therefore,
according to this invention, loading port 2312 is not directly over
reservoir electrode 2310 and fluid path 2316 is provided by which
fluid may flow to the reservoir electrode 2310 for filling. In this
way, the variability of the fluid volume at the reservoir may be
reduced, preferably entirely eliminated, as indicated by less
impedance measurement variability during filling and/or use.
FIGS. 23A and 23B illustrate top views of an electrode arrangement
2400 and an electrode arrangement 2420, respectively, which are
examples of electrode configurations for helping to detect whether
a sample reservoir is fully loaded. Currently, when an on-actuator
reservoir is filled, it may be difficult to determine with great
accuracy the amount of fluid at the reservoir. This invention
provides a separate electrode at the fringe of the primary storage
reservoir for measuring impedance in order to verify that the
reservoir is fully loaded (i.e., not underloaded).
In one example, electrode arrangement 2400 of FIG. 23A includes a
reservoir electrode 2410. Reservoir electrode 2410 may be
associated with an on-actuator reservoir. One side of reservoir
electrode 2410 feeds a line, path, and/or array of droplet
operations electrodes 2412 (e.g., electrowetting electrodes). An
elongated impedance electrode 2414 is provided along the side of
reservoir electrode 2410 that is opposite the droplet operations
electrodes 2412. The impedance electrode 2414 is a separate
electrode at the fringe of the primary storage reservoir. Using
impedance detection, one may verify that liquid is atop impedance
electrode 2414, which provides assurance that the associated
reservoir is fully loaded. For example, when a certain expected
impedance measurement that indicates liquid atop impedance
electrode 2414 is read at impedance electrode 2414, this indicates
that the reservoir is fully loaded. However, when the impedance
measurement indicates little or no liquid atop impedance electrode
2414, this indicates that the reservoir may be underloaded.
In another example, electrode arrangement 2420 of FIG. 23B includes
a reservoir electrode 2422. Reservoir electrode 2422 may be
associated with an on-actuator reservoir. One side of reservoir
electrode 2422 feeds a line, path, and/or array of droplet
operations electrodes 2424 (e.g., electrowetting electrodes). In
this example, a triangular-shaped impedance electrode 2426 is
provided at one of the corners of reservoir electrode 2422 that is
opposite the droplet operations electrodes 2424. Again, the
impedance electrode 2426 is a separate electrode at the fringe of
the primary storage reservoir. Using impedance detection, one may
verify that liquid is atop impedance electrode 2426, which provides
assurance that the associated reservoir is fully loaded. While
FIGS. 23A and 23B describe examples of a single impedance electrode
at one location with respect to the primary storage reservoir,
FIGS. 24A, 24B, and 24C describe examples of impedance electrodes
at multiple locations of the primary storage reservoir.
FIGS. 24A, 24B, and 24C illustrate top views of an electrode
arrangement 2500, an electrode arrangement 2520, and an electrode
arrangement 2540, respectively, which are more examples of
electrode configurations for helping to detect whether a sample
reservoir is fully loaded.
In one example, electrode arrangement 2500 of FIG. 24A includes a
reservoir electrode 2510. Reservoir electrode 2510 may be
associated with an on-actuator reservoir. One side of reservoir
electrode 2510 feeds a line, path, and/or array of droplet
operations electrodes 2512 (e.g., electrowetting electrodes). A
U-shaped impedance electrode 2514 is provided along the three sides
of reservoir electrode 2510 that do not feed droplet operations
electrodes 2512. Again, the impedance electrode 2514 is a separate
electrode at the fringe of the primary storage reservoir. Using
impedance detection, one may verify that liquid is atop impedance
electrode 2514, which provides assurance that the associated
reservoir is fully loaded.
In another example, electrode arrangement 2520 of FIG. 24B includes
a reservoir electrode 2522. Reservoir electrode 2522 may be
associated with an on-actuator reservoir. One side of reservoir
electrode 2510 feeds a line, path, and/or array of droplet
operations electrodes 2524 (e.g., electrowetting electrodes).
Reservoir electrode 2522 is flanked by two elongated impedance
electrodes 2526 (e.g., impedance electrodes 2526a and 2525b).
Again, impedance electrodes 2526a and 2525b are separate electrodes
at the fringe of the primary storage reservoir. Using impedance
detection, one may verify that liquid is atop impedance electrodes
2526a and 2525b, which provides assurance that the associated
reservoir is fully loaded.
In yet another example, electrode arrangement 2540 of FIG. 24C
includes a reservoir electrode 2542. Reservoir electrode 2542 may
be associated with an on-actuator reservoir. One side of reservoir
electrode 2542 feeds a line, path, and/or array of droplet
operations electrodes 2544 (e.g., electrowetting electrodes). In
this example, four triangular-shaped impedance electrodes 2546
(e.g., impedance electrodes 2546a, 2546b, 2546c, and 2546d) are
provided at the four corners of reservoir electrode 2542. Again,
impedance electrodes 2546a, 2546b, 2546c, and 2546d are separate
electrodes at the fringe of the primary storage reservoir. Using
impedance detection, one may verify that liquid is atop impedance
electrodes 2546a, 2546b, 2546c, and 2546d, which provides assurance
that the associated reservoir is fully loaded.
6.3 Systems
It will be appreciated that various aspects of the invention may be
embodied as a method, system, computer readable medium, and/or
computer program product. Aspects of the invention may take the
form of hardware embodiments, software embodiments (including
firmware, resident software, micro-code, etc.), or embodiments
combining software and hardware aspects that may all generally be
referred to herein as a "circuit," "module" or "system."
Furthermore, the methods of the invention may take the form of a
computer program product on a computer-usable storage medium having
computer-usable program code embodied in the medium.
Any suitable computer useable medium may be utilized for software
aspects of the invention. The computer-usable or computer-readable
medium may be, for example but not limited to, an electronic,
magnetic, optical, electromagnetic, infrared, or semiconductor
system, apparatus, device, or propagation medium. The computer
readable medium may include transitory and/or non-transitory
embodiments. More specific examples (a non-exhaustive list) of the
computer-readable medium would include some or all of the
following: an electrical connection having one or more wires, a
portable computer diskette, a hard disk, a random access memory
(RAM), a read-only memory (ROM), an erasable programmable read-only
memory (EPROM or Flash memory), an optical fiber, a portable
compact disc read-only memory (CD-ROM), an optical storage device,
a transmission medium such as those supporting the Internet or an
intranet, or a magnetic storage device. Note that the
computer-usable or computer-readable medium could even be paper or
another suitable medium upon which the program is printed, as the
program can be electronically captured, via, for instance, optical
scanning of the paper or other medium, then compiled, interpreted,
or otherwise processed in a suitable manner, if necessary, and then
stored in a computer memory. In the context of this document, a
computer-usable or computer-readable medium may be any medium that
can contain, store, communicate, propagate, or transport the
program for use by or in connection with the instruction execution
system, apparatus, or device.
Program code for carrying out operations of the invention may be
written in an object oriented programming language such as Java,
Smalltalk. C++ or the like. However, the program code for carrying
out operations of the invention may also be written in conventional
procedural programming languages, such as the "C" programming
language or similar programming languages. The program code may be
executed by a processor, application specific integrated circuit
(ASIC), or other component that executes the program code. The
program code may be simply referred to as a software application
that is stored in memory (such as the computer readable medium
discussed above). The program code may cause the processor (or any
processor-controlled device) to produce a graphical user interface
("GUI"). The graphical user interface may be visually produced on a
display device, yet the graphical user interface may also have
audible features. The program code, however, may operate in any
processor-controlled device, such as a computer, server, personal
digital assistant, phone, television, or any processor-controlled
device utilizing the processor and/or a digital signal
processor.
The program code may locally and/or remotely execute. The program
code, for example, may be entirely or partially stored in local
memory of the processor-controlled device. The program code,
however, may also be at least partially remotely stored, accessed,
and downloaded to the processor-controlled device. A user's
computer, for example, may entirely execute the program code or
only partly execute the program code. The program code may be a
stand-alone software package that is at least partly on the user's
computer and/or partly executed on a remote computer or entirely on
a remote computer or server. In the latter scenario, the remote
computer may be connected to the user's computer through a
communications network.
The invention may be applied regardless of networking environment.
The communications network may be a cable network operating in the
radio-frequency domain and/or the Internet Protocol (IP) domain.
The communications network, however, may also include a distributed
computing network, such as the Internet (sometimes alternatively
known as the "World Wide Web"), an intranet, a local-area network
(LAN), and/or a wide-area network (WAN). The communications network
may include coaxial cables, copper wires, fiber optic lines, and/or
hybrid-coaxial lines. The communications network may even include
wireless portions utilizing any portion of the electromagnetic
spectrum and any signaling standard (such as the IEEE 802 family of
standards, GSM/CDMA/TDMA or any cellular standard, and/or the ISM
band). The communications network may even include powerline
portions, in which signals are communicated via electrical wiring.
The invention may be applied to any wireless/wireline
communications network, regardless of physical componentry,
physical configuration, or communications standard(s).
Certain aspects of invention are described with reference to
various methods and method steps. It will be understood that each
method step can be implemented by the program code and/or by
machine instructions. The program code and/or the machine
instructions may create means for implementing the functions/acts
specified in the methods.
The program code may also be stored in a computer-readable memory
that can direct the processor, computer, or other programmable data
processing apparatus to function in a particular manner, such that
the program code stored in the computer-readable memory produce or
transform an article of manufacture including instruction means
which implement various aspects of the method steps.
The program code may also be loaded onto a computer or other
programmable data processing apparatus to cause a series of
operational steps to be performed to produce a processor/computer
implemented process such that the program code provides steps for
implementing various functions/acts specified in the methods of the
invention.
7 CONCLUDING REMARKS
The foregoing detailed description of embodiments refers to the
accompanying drawings, which illustrate specific embodiments of the
invention. Other embodiments having different structures and
operations do not depart from the scope of the present invention.
The term "the invention" or the like is used with reference to
certain specific examples of the many alternative aspects or
embodiments of the applicants' invention set forth in this
specification, and neither its use nor its absence is intended to
limit the scope of the applicants' invention or the scope of the
claims. This specification is divided into sections for the
convenience of the reader only. Headings should not be construed as
limiting of the scope of the invention. The definitions are
intended as a part of the description of the invention. It will be
understood that various details of the present invention may be
changed without departing from the scope of the present invention.
Furthermore, the foregoing description is for the purpose of
illustration only, and not for the purpose of limitation.
* * * * *
References